2016年免疫治疗研究（来自PUBMED部分）
免疫学(imunology) 是研究免疫系统结构与功能的学科，涉及免疫识别、免疫应答、免疫耐受、免疫调节等的规律与机制研究以及免疫机制在相关疾病发生发展中的作用和免疫学技术在疾病诊断、治疗与预防中的应用。http://www.ncbi.nlm.nih.gov/pubmed/27426915Sci Rep. 2016 Jul 18;6:29914. doi:10.1038/srep29914.Tumourhypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1and M2-like macrophages.缺氧诱导黑色素瘤生长和转移的内在机制是：因缺氧释放高迁移率族蛋白1（HMGB1），HMGB1再通过晚期糖基化终末产物受体（RAGE）提升M2型巨噬细胞的积累，增加IL-10的产生。（有研究利用小鼠结直肠癌手术模型发现，腹部手术创伤能够引起大量高迁移率族1 ( HMGB1 ) 在小鼠腹腔释放，进而招募大量MDSC，从而促进切除术后结肠癌的腹膜转移。此外， 有研究报道TNYR-2 信号，而非TNFR -l ，能够通过上调MDSC 中FLICE 抑制蛋白( c- FLIP ) 并抑制caspase -8 活性，从而促进MDSC 存活和外周的募集。）http://www.ncbi.nlm.nih.gov/pubmed/27425593Oncogene. 2016 Jul 18. doi: 10.1038/onc.2016.231.Integratingconventional and antibody-based targeted anticancer treatment intoimmunotherapy.密集传统放疗化疗损伤患者的免疫力。研究发现常规治疗后宿主T细胞对肿瘤特异性抗原产生正常的敏感性，整合细胞毒治疗最大限度抑制肿瘤。但源于肿瘤的损伤相关分子模式（DAMP）随之敏感，驱动I型干扰素IFN1增加，促使CD8+T细胞蓄势待发。这样一些放化疗反而可以增加肿瘤渗透性的淋巴细胞TIL克服免疫治疗的耐药。（CD8+T细胞：中科院生物物理所王盛典实验室与美国芝加哥大学傅阳心实验室合作在Cancer Cell上发表论文，报道了HER2抗体抗肿瘤效应的新机制。传统观点认为HER2 抗体治疗乳腺癌是基于其阻断致癌信号或诱导ADCC 效应。他们证明， HER2抗体的抗肿瘤效应为T 细胞依赖性的。深入研究发现， HER2 抗体可促进肿瘤特异性CD8+T 细胞应答及记忆， 并促进HMGß-I 诱导的MyD88 活化。此研究为肿瘤免疫治疗提供了新的理论基础及研究思路。）http://www.ncbi.nlm.nih.gov/pubmed/27424476Pancreatology. 2016 Jul 11. pii: S1424-3903(16)31147-4.doi: 10.1016/j.pan.2016.07.008. Monitoringand functional characterization of the lymphocytic compartment in pancreaticductal adenocarcinoma patients.胰腺导管癌患者相应CD4+ 无记忆和调节性T 细胞被增强，但与正常人相比免疫细胞数还是低。在胰腺导管癌双特异性内膜上γδT细胞比αβT细胞积累数量更多，表明γδT 细胞渗透进肿瘤。抗肿瘤细胞毒哪怕小量T细胞和NK细胞被双特异性靶向CD3+ T 细胞抗HER2的抗体或曲妥珠单抗所诱导。重要的是，一定数量的 γδ T细胞对参与γδ T细胞受体的双特异性抗体杀死大量肿瘤细胞是必须的。 （与其他非常规的T 细胞类似， γδT 细胞识别某些保守的非膜和膜类抗原。这些抗原一般由应激性细胞上调表达，其表达形式和分布与PRR 所识别的病原体相关分子模式( pathogen asociated molecularpattern ,PAMP) 或危险相关分子分子模式( danger-associated molecular pattern , DAMP ) 相类似。γδT细胞的抗原或配体识别无需MHC分子的辅佐， 采取B 细胞受体(膜型免疫球蛋白，mIg) 样的直接识别方式。在功能发挥的方式上，γδT细胞兼具T辅助细胞(Th) 和细胞毒T细胞的双重细胞效应:可在不同性质的微生物抗原剌激下分泌Th1或Th2 型细胞因子; 直接识别靶细胞( 肿瘤细胞或病毒感染细胞)表面抗原后产生即时的细胞毒效应。γδT细胞在外周T淋巴细胞库中所占比例较少，但在黏膜上皮组织中却有较多的富集。由于其快捷反应和综合性功能， γδT细胞被视为免疫防御和免疫监视的第一道重要防线。当γδT细胞发挥作用后，可通过自身抗原提呈细胞(APC) 样的效应， 或通过所分泌的细胞因子效应进一步诱导或促进特异性T细胞应答。由于具有上述特性，一般认为γδT细胞在功能上起到连接天然免疫与获得性免疫的桥梁作用，并对应激所致变化做出快速应答， 产生固有免疫保护性应答，维护自身稳定。人类γδT细胞的组织分布。尽管γδT细胞仅占人外周血淋巴细胞的很少部分，但在人小肠上皮间淋巴细胞(intraepilhelial Lymphocyte ,IEL)中的组分可达1 0 % - 18 % ，在人大肠IEL中的比例可高达25 % -37 % ，这一分布提示它们可能在黏膜免疫过程中起重要作用。γδT细胞具有不同于αβT细胞的抗原识别分子机制和能力。研究发现，γδT细胞能识别一系列不同的抗原，包括来自自身或外界、大或小、膜类和非膜类分子等。与αβT细胞识别的抗原相比， γδT细胞所识别的抗原类似于抗体识别的抗原。其识别方式是直接结合性的，大多数情况下无需抗原提呈分子。由于γδT细胞识别的抗原数量较少，并且为多克隆应答，具有NKT 细胞样反应特点，故其抗原也称之为TCRγδ配体。此外， 有证据表明，许多单个γδT细胞具有多重特异性，它们可能使用不同模式进行不同配体的识别。这种反应模式除了影响机体自身稳定与耐受外，还可使γδT细胞反应出现效应重叠，从而产生更高效的整体应答。肿瘤组织中有大量T细胞的浸润，即TlL，而有关TI L 的浸润机制尚不清楚。Cai 等利用免疫组化方法，对342例肝细胞痛( HCC ) 患者癌和癌旁组织浸润的γδT细胞进行染色分析， 发现与癌组织相比，癌旁组织中浸润的γδT细胞反而较多， 且癌旁组织γδTIL 数量与患者的复发率呈负相关。 因此这可作为术后预测复发的指标，也提示γδT细胞似于在围剿肿瘤细胞，使其不易扩散。研究发现.促炎性趋化因子CCL2及其受体CCR2 是肿瘤微环境中γδT细胞迁移和浸润的重要决定因素。另外，它作为一个多功能的因子， 不仅发挥抑制肿瘤作用(募集细胞毒性T细胞、NK细胞) ，也通过MDSC ( 髓源抑制细胞)、TAM ( 肿瘤相关巨噬细胞)等起免疫抑制作用。早前的研究一直认为，浸润到肿瘤局部的γδT细胞都是来杀伤肿瘤的，对抗肿瘤免疫应答是有利的。直到发现调节性γδT细胞(γδTreg) ，人们才逐渐认识到肿瘤微环境中的γδT细胞除了抗肿瘤的功能亚群以外，尚存在发挥调节作用的亚群。γδTreg 目前已在众多人类肿瘤组织中被发现。然而，其抑制机制不甚明了。近有发现，乳腺癌细胞诱导的γδTreg 可在肿瘤微环境中使效应性T细胞和DC 衰老，导致其表型变化和功能缺失，总体上表现为较强的免疫抑制作用。γδT可分泌I L- 17 ,研究发现γδTreg细胞分泌的I L- 1 7 可诱导肿瘤细胞产生CXC 15 ，而髓源抑制细胞( MDSC) 通过CXC L5/ CXCR2依赖的方式浸润到肿瘤组织。IL-17也加强了MDSC在肿瘤微环境中的免疫抑制作用，而且MDSC通过分泌IL- 1ß和lL-23，诱导产生更多分泌IL-17 的γδTreg，IL-17 也反馈性地加强了MDSC 分泌IL-lβ和lL-23.）http://www.ncbi.nlm.nih.gov/pubmed/27424146Cytotherapy. 2016 Jul 13. pii: S1465-3249(16)30437-6.doi: 10.1016/j.jcyt.2016.06.010. AutocrineCCL19 blocks dendritic cell migration toward weak gradients of CCL21.趋化因子CCL19对高自分泌(1型 DC) 比低自分泌 (前列腺素 E2 -DCs)更明显导致从外周血到淋巴组织归巢损伤。与CCL21相比，CCL19负调节DC细胞归巢能力。（趋化性细胞因子( chemokine , chemoattactant cytokine , CK) 是长度为8 - 12kDa 具有使细胞分化、迁移和运输功能的多肽。趋化因子是一类具有趋化特性的细胞因子蛋白样物质，能够激活趋化因子受体，目前已经发现50 多种，依据分子中4 个保守的半胱氨酸( cysleine , Cy s) 的位置不同它们被分成了四个家族， 即CXC 、CX3C 、CC 、c 。趋化因子的功能主要是趋化各种细胞，它们直接参与自细胞特别是吞噬细胞和淋巴细胞的游走和活化， 在炎症反应中起核心作用。）http://www.ncbi.nlm.nih.gov/pubmed/27420991GenetMol Res. 2016 Jul 14;15(2). doi: 10.4238/gmr.15027419.Expressionof toll-like receptors in hepatic cirrhosis and hepatocellular carcinoma.通过识别多个微生物分子结构模式，TLR（Toll-like receptors ) 能够特异识别病理相关分子模式 (PAMP) 。各种各样的TLRs表达与肝实质和非实质细胞表面。Kupffer细胞是一类肝非实质巨噬细胞，与肝纤维化的严重程度相关。通过上调组织抑制因子金属蛋白酶的表达和下调MMP活性，Kupffer细胞在细胞外基质的合成与沉淀中起重要作用。肝硬化是由于不停地损伤修复而引起的纤维化病并导致肝癌的发生。多类型TLR 如TLR2, TLR3, TLR4, and TLR9, 还有其他受体在肝硬化和肝癌表达。酒精、乙肝、丙肝等造成慢性和重复肝损伤能被TLR识别。这是通过PAMP 信号通路直接增加肝硬化和肝癌的风险程度。（TLR在识别PAMP 中起重要作用，是一种重要的模式识别受体，主要表达于巨|噬细胞和树突状细胞(dendritic cell , DC) 表面.构成机体抵御病原体入侵的第一道屏障。TLR 是一种进化上高度保守的I 型跨膜蛋白，目前发现并克隆了十多种哺乳动物的T LR 分子，它们选择性识别不同的PAMP 分子，如TLR2 、TLR3 、1'LR4 、TLR5、TLR9分别识别病原微生物的LTA 、dsRNA 、LPS ，nagellin 、CpG基序。目前已报道了1 1 种人TLR 和13 种小鼠TLR 。根据不同的亚细胞定位， TLR 可以分为细胞膜表面TLR( 主要包括TLR1 、TL R2、TLR4 、TLR5、TLR6 等)和细胞内TLR ( 目前发现的有TLR3、TLR7 /8 、TLR9) 两大类。TLR 与各自配体结合后可通过大致相似的信号转导途径诱导目的基因的活化表达，但不同T LR 因其结合相对特异的接头蛋白而激发相应的生物学效应。目前公认的TLR 信号通路根据接头蛋白的不同分为MyD88 (myeloid differentfactor 88) 依赖和T阳F 依赖(或者称为MyD88 非依赖)两条不同的信号转导途径。）http://www.ncbi.nlm.nih.gov/pubmed/27418644Blood. 2016 Jul 14. pii: blood-2016-03-707547.Osteoclastspromote immune suppressive microenvironment in multiple myeloma: therapeuticimplication.破骨细胞OC通过直接抑制CD4+ 和CD8+ T细胞增殖保护多发性骨髓瘤抗T细胞调节的细胞毒。在破骨细胞生成过程中，免疫检查点分子PDL1, Galectin-9, HVEM, and CD200, 以及T 细胞代谢调节子IDO 和CD38 明显上调。抗PDL1单克隆抗体和IDO抑制剂部分克服破骨细胞抑制的T细胞对多发性骨髓瘤的应答能力。 证明了OC对T细胞的抑制作用。此外，在破骨细胞生成过程中，主要由OC分泌的Galectin-9和 增殖诱导的配体 (APRIL)明显上调， Galectin-9 特别诱导T细胞凋亡而对单核细胞和骨髓瘤细胞无损，APRIL诱导PDL1表达为OC提供额外的免疫抑制，而且CD38 明显上调。使用抗CD38 单克隆抗体，缓解 T细胞被抑制的功能，下调HVEM and IDO. 总之, 在多发性骨髓瘤骨转过程中抑制OC涉及的多个免疫蛋白和生长因子是基本的要求。http://www.ncbi.nlm.nih.gov/pubmed/27417188JImmunotoxicol. 2016 Jul 15:1-9. Effectof administration timing of postchemotherapy granulocyte colony-stimulatingfactor on host-immune cell recovery and CD8+ T-cell response.粒性白血球集落刺激因子G-CSF在老鼠模型的化疗后，通过注射时间的调节影响免疫细胞的恢复。老鼠一次性注射环磷酰胺 (4 mg/mouse; CTX) 然后每天注射 G-CSF (5 g/mouse) 从CTX注射后1-5天, 2-5天 or 5-9天 。各类免疫细胞在CTX 注射后第7天，9天，12天进行分析。白细胞数量、中性粒细胞数量、单核细胞数量、淋巴细胞数量、粒性白血球数量、树突状细胞数量明显增多在G-CSF 注射方案2-5，而且不影响CD8+ T细胞扩张.http://www.ncbi.nlm.nih.gov/pubmed/27401477IntImmunol. 2016 Jul 8. pii: dxw030. Cancer-inducedheterogeneous immunosuppressive tumor microenvironments and their personalizedmodulation.虽然PD-1等免疫治疗取得巨大进步。但免疫治疗存在的最大障碍是患者身体出现的免疫抑制。存在2种类型的免疫抑制。一是癌症基因改变诱导的，二是肿瘤特异性T细胞触发的局部适应性免疫抑制。前者由多免疫抑制分子多机制引起，通过基因改变触发，包括致癌基因激活。免疫抑制机制涉及不同肿瘤亚型个人情况通过不同的信号通路。个性化治疗非常必要。（免疫抑制（immunosuppression）：是指对于免疫应答的抑制作用。免疫力低下容易受到细菌、病毒、真菌等感染，甚至容易长肿瘤。但是免疫超常也会对身体产生损害，如很多自身免疫性疾病就是因为自身免疫力表达异常，把机体正常组织当作攻击对象，造成机体的损害。）http://www.ncbi.nlm.nih.gov/pubmed/27400792StemCells Transl Med. 2016 Jul 11. pii: sctm.2015-0243. HumanMesenchymal Stem Cells Impact Th17 and Th1 ResponsesThrough a Prostaglandin E2 and Myeloid-Dependent Mechanism.前列腺素E2(PGE2)依赖和骨髓细胞调节的新机制，人间质干细胞MSC据此相互诱导Th17 而抑制Th1应答。意味着利用MSC监控、治疗多发性硬化和其他免疫相关疾病。（Th0细胞在IL-12等细胞因子作用下分化而成，Th1细胞为CD4阳性细胞，主要分泌IL-2（白细胞介素2）、IFN-γ（γ干扰素）、TNF（β肿瘤坏死因子）等。功能为参与调节细胞免疫，辅助细胞毒性T细胞分化，介导细胞免疫应答，参与迟发型超敏反应等。Th1，Th2，Th3，和Th17细胞同属于Th0分化的不同的Th细胞亚群。主要是增强吞噬细胞介导的抗感染免疫，特别是抗胞内病原体的感染。IFN-γ（γ干扰素）活化巨噬细胞，增强其杀伤已被吞噬的病原体的能力。还能促进IgG的生成。TH1辅助细胞主要为对抗细胞内细菌及原虫的免疫反应，其主要为白介素12(IL-12)所驱动诱发，其主要的执行的细胞因子是伽马干扰素(IFN-γ)，其最重要的执行细胞为巨噬细胞(Macrophage)另外还有杀手CD8+T细胞、产生IgG的B细胞以及分泌IFNg的CD4+ T细胞等、其主要的转录因子为STAT4 另外还有T-bet等等 。CD4+T细胞分泌的IFNg会活化巨噬细胞，使其能够吞噬并消化掉细胞内细菌及原虫，另外IFNg也会活化iNOS而放出NOx等自由基而直接杀死细胞内细菌及原虫，TH1免疫反应对应的是第四型自体免疫疾病(Type4 delayed typehypersensitivity)也就是过分的TH1激活将会导致巨噬细胞自体免疫疾病比如麻风病或结核菌素过分反应或第一型糖尿病等都属此类。辅助性T 细胞17(T helper cell 17, Th17)是一种新发现的能够分泌白介素17(interleukin 17, IL-17)的T 细胞亚群，在自身免疫性疾病和机体防御反应中具有重要的意义。β转化生长因子 (transforming growth factorb, TGF-β)、IL-6、IL-23 和IL-21 在Th17 细胞的分化形成过程中起着积极的促进作用，而γ干扰素 (interferon γ, IFN-γ)、IL-4、细胞因子信号传送抑制蛋白3(suppressor of cytokinesignaling 3, Socs3)和IL-2则抑制它的分化。TH17免疫反应对应的是第三型自体免疫疾病(Type3 Immune complex & complementhypersensitivity)也就是过分的TH17激活将会导致中性球自体免疫疾病比如类风湿性关节炎或Arthus反应等都属此类。）http://www.ncbi.nlm.nih.gov/pubmed/27396959Immunity. 2016 Jul 19;45(1):46-59. doi: 10.1016/j.immuni.2016.06.007.Epub 2016 Jul 5.RIPK1and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-likeReceptor 4.巨噬细胞是人体天然免疫系统的一个重要组成部分，对病原体敏感并产生局部或全身的炎性反应。丝氨酸苏氨酸激酶1受体相互作用蛋白RIPK1 和 RIPK3 是同源激酶,以前认为其与肿瘤坏死有关。本研究描述其为脂多糖诱导的促炎基因表达主要调控酶。原初巨噬细胞的调节功能是在缺乏caspase-8活性,需要接头分子TRIF并以自主的方式进行。RIPK1 和 RIPK3激酶提升炎性变化所必须的 Erk, cFos, and NF-κB持久活性。体内RIPK1和RIPK3 主调节脂多糖诱导的急性炎症反应。这种调控无需caspase各种各样操作. 本文发现一条炎性病理途径。(T LR 识别PAMP 后，启动一系列胞内级联信号活化， 诱导目的基因活化表达，但每个TLR 又因选择性结合相对特异的接头蛋白而具有各自的信号转导特性.根据接头分子的不同，TLR 的信号转导主要分为两条途径，即MyD88 ( myeloid differentfactor 88) 依赖和TRIF ( TIR domain containing adaptor inducing inlerferon-ß) 依赖(或者称为MyD88 非依赖)的信号转导途径。在My D88 依赖性途径中，当相应配体同TLR结合后可，通过TLR 受体本身胞内段的TIR 结构域募集同样含有TIR 结构域的接头分子MyD88 、随后通过My D88 的死亡结构域( Death domain , DD ) 与IRAK ( IL-1 receptor-associatedkinase) 家族蛋白分子结合成为信号转导复合物。该复合物继续募集并活化下游TRAF6 分子，TRAF6的活化能够引起两条不同途径的信号转导: 一条途径包括p38 ，JNK 、ERK 的MAPK 家族分子;另一条是Rel 家族转录因子NF- KB 途径， 最终激活相关炎性细胞因子和I 型干扰素的基因表达。而MyD88 非依赖途径则是通过接头分子TRIF或者TRAM 募集TRAF3 和TRAF6 ，分别通过TBK l 和TA KI 诱导NF-KB 的晚期活化和l RF-3 的磷酸化和核转位，继而调控炎性细胞因子和I型干扰素的表达， 此信号途径可见于TLR3 或TLR4 的活化过程。TLR 信号不仅能够启动和控制炎症反应的性质、强度和持续时间，从而在激活天然免疫中发挥重要的作用， 而且还可通过对抗原提呈细胞的调节，指导抗原特异性免疫反应， 是连接天然免疫和获得性免疫的桥梁.)(肿瘤坏死因子（Tumor necrosis factor，TNF）根据接收的环境信号，刺激细胞死亡或存活。在这个过程中，有两个关键的蛋白：受体相互作用蛋白1(RIP1)和受体相互作用蛋白3(RIP3)，形成复合物的形式激发坏死。研究显示，这两种蛋白及其激酶参与触发了细胞死亡和炎症过程，造成许多疾病中的严重后果。 近期两个研究组围绕受体相互作用蛋白激酶RIPK1和RIPK3展开了研究，发现前者能阻断Caspase-8 和RIPK3介导的一种致命性死亡，另外RIPK1也在细胞决定生或死，以及选择如何死去过程中起至关重要的作用。 RIPK1 对抑制坏死性凋亡至关重要，而且也发现RIPK1对骨髓移植后维持造血干细胞的存活起至关重要的作用。考虑到RIPK1靶向治疗这一研究发现尤其的重要，因为其有可能会对机体的其他细胞造成不必要的副作用。因此，确保严格地调查所有潜在药物的脱靶效应非常的重要。)http://www.ncbi.nlm.nih.gov/pubmed/27392648Cancer Lett. 2016 Jul 5. pii: S0304-3835(16)30395-0.doi: 10.1016/j.canlet.2016.07.001. Prospectsfor chimeric antigen receptor (CAR) γδ T cells: Apotential game changer for adoptive T cell cancer immunotherapy.免疫治疗的一种方法是嵌合抗原受体(CAR)治疗晚期癌症尤其是常规治疗难治的。虽然在血液恶性肿瘤取得长足进步，但实体瘤进展有限，可能是由于实体瘤微环境的免疫抑制。现今T细胞带有αβ受体已被用于生成 CAR T 细胞. 本文强调γδ T 与αβ T 的不同生理学特征包括上皮组织归巢、粘膜组织归巢以及独特直接识别抗原的能力，缺乏同种异体反应，递呈抗原能力。这些 γδ T细胞有希望用于几类实体瘤治疗包括黑色素瘤和肠胃癌。 工程化 γδ T 细胞可能被看作过继T细胞治疗粘膜肿瘤的新平台。（嵌合抗原受体(chimeric antigen receptor ，CAR ) ， 有时也称为T小体(T- bod y) ，是一种人工合成的嵌合型的免疫受体。CA R通常来源于抗肿瘤单抗， 是另一种赋予转基因T 细胞特异性的方式.嵌合型受体的结构包括四种元件。靶向结构域来源于单链抗体( scFv) ， 负责识别肿瘤抗原. 它与跨膜区由一段胞外铰链区相连接。CA R 的胞内区通常包含与T 细胞活化增殖相关的信号转导结构域，如 C D33-ζ、CD28 及4- IBB 分子的信号转导结构城等。这四种元件中的每一种都起着不可或缺的作用。当CA R 结合靶细胞表面的肿瘤相关抗原后， CAR 胞内区会转导T 细胞相关激活信号。被激活的T 细胞进而裂解靶细胞或诱导靶细胞凋亡。TCR 识别的是由HLA 递呈的来源于抗原的多肽段，与之不同的是，CAR 则识别完整的细胞表面抗原。所以， CAR 的识别是HLA 非限制性的，但是却要求抗原必须是细胞表面的抗原。所有胞内的突变蛋白都不能作为基于CAR 的过继性治疗的靶点。）http://www.ncbi.nlm.nih.gov/pubmed/27378625ChemBiol Interact. 2016 Jul 1;256:111-124. doi:10.1016/j.cbi.2016.06.027. Oxidativestress, polarization of macrophages and tumour angiogenesis: Efficacy ofcaffeic acid.巨噬细胞极化是应对微环境信号表达不同功能程序的过程。形成2个极端M1 and M2 巨噬细胞. M1巨噬细胞通过增强杀死和吞噬能力而具有很强抗病原体和肿瘤能力，上调促炎细胞因子和活性分子簇，递呈抗原; M2 巨噬细胞和与肿瘤有关的巨噬细胞 (TAMs) 调节组织重构、促进组织修复和血管生成，扩大代谢通路，抑制相应免疫应答。已证明ROS 产生对M1巨噬细胞激活和功能是关键的，对M2巨噬细胞和TAM分化也是必须的。在老鼠癌症模型抗氧化治疗可以阻塞TAM分化和肿瘤发生。咖啡酸天然抗氧化剂影响巨噬细胞功能、极化、血管生成、肿瘤生长。抗氧化剂是一个潜在的治疗肿瘤办法。(近年来，对巨噬细胞的研究主要着重于其异质性的研究。其异质性主要是由于到达组织后未分化的循环单核细胞的异质性以及巨噬细胞所在的微环境所决定的。巨噬细胞由正常状态下或炎症时从外周血迁移至组织中的单核细胞分化而来。巨噬细胞对损伤或感染发生迅速的反应，活化后的巨噬细胞分化为两个不同的亚群: Ml 和M2。I型炎症因子和微生物的代谢产物活化的巨噬细胞称为M 1型巨噬细胞;M2型巨噬细胞由于表达不同的活化标志而被分成三个亚群: M2 a ，由IL-4 或IL-13 诱导;M2b由免疫复合体和TLR 或IL- 1 R 的激动剂诱导; M2c ，由IL-10和糖皮质激素诱导。M 1 和M2在受体表达、细胞因子分泌以及效应性功能方面差异很大。 M1 型巨噬细胞具有杀灭微生物及促炎症作用。M2 型巨噬细胞具有很强的免疫调节作用和组织修复能力而其杀灭做生物功能很弱。因此， 巨噬细胞的活化可以是促炎的，也可以是抗炎的。M I 和M2 代表的是巨噬细胞的两个极端和简化的功能状态，实际上巨噬细胞的活化是一个连续的功能状态的复杂过程。)http://www.ncbi.nlm.nih.gov/pubmed/27367184JClin Invest. 2016 Jul 1;126(7):2404-11. doi: 10.1172/JCI86892.Epub 2016 Jul 1.Thehost STING pathway at the interface of cancer and immunity.大多数人癌症存在天然适应免疫功能，表现在肿瘤微环境存在肿瘤抗原特异性CD8+ T 细胞渗透。但对此也发现问题，在不存在各种各样感染病原体的情况下，天然免疫敏感通路可以监测到癌症的存在并导致天然适应免疫应答？但I型 IFN产生表明癌症触发其他天然免疫敏感通路诱导I型 IFN产生。于是，STING通路在此主要角色浮出水面。在肿瘤浸润DC（tumor-infiltrating DCs）胞质里STING对胞质肿瘤DNA敏感。激活STING与IFN-β产生和诱导抗癌T细胞有关。 STING拮抗剂扩大和优化STING治疗癌症的活化作用 。老鼠模型效果显著，I期临床试验正在进行中。（外源性或内源性DNA 触发的STING( stimulator of interferongene) 活化是激活天然免疫应答的关键环节，然而STING 过度活化会产生免疫损伤。是越来越多的研究发现， STING 是胞内DNA 诱导产生I 型干扰素所必需的信号分子，在识别DNA 的过程中也发挥重要作用，目前人们已经对STING在这些天然免疫信号通路中作用的机制有了较深的认识.STING可能并不是D NA 识别分子，目前没有研究发现其能直接结合DNA ，同时其也不含有明显的DNA 结合域。STlNG 含有多重跨膜区，能够活化IRF3 通路，提示其可能为一种接头分子或骨架蛋白，但还需要借助细胞内其他模式识别受体，所以STING主要作为通路的中间分子发挥作用。有趣的是，研究人员发现STING 在接受剌激后，能够从内质网转位到点状的核周结构中， 但是这种转位的意义还不清楚。DDX41 能在髓样树突状细胞胞浆中与外源性DNA及STING 蛋白结合， 并且依赖于STING 通过其死亡结构域，介导TBKI 、IRF3和NF-KB 活化，诱导I型IFN 产生.）http://www.ncbi.nlm.nih.gov/pubmed/27357153J Immunol. 2016 Aug 1;197(3):795-806. doi:10.4049/jimmunol.1600262. Epub 2016 Jun 29.NKCell Activation in the Antitumor Response Induced by IFN-α Dendritic CellsLoaded with Apoptotic Cells from Follicular Lymphoma Patients.滤泡性淋巴瘤 (FL)是懒惰性非霍奇金瘤的一种常见形式。FL被看作无法治愈、虽对治疗很敏感，也频繁复发。本文研究因存在IFN-α and GM-CSF (IFN-DC)而生成的源于单核细胞的负载凋亡淋巴细胞的树突状细胞DC激活抗FL的免疫应答能力。最终目的是设计针对特定患者新疫苗治疗FL. 来自患者的凋亡肿瘤细胞负载IFN-DC，其与人体自有淋巴细胞一起培养2周， 导致Th1非对称应答，基于显著高水平的IFN-γ产生和 CD8(+) 及NK 细胞惊人的增加频率，增强对自体FL的细胞毒效应能力。在近乎没有IL-10的情况下，IFN-DC 有效促进NK细胞激活, 增加细胞毒性受体的表达，IFN-γ大量产生。而且，通过激活来自FL患者的NK细胞直接识别和杀死淋巴瘤细胞。也证明MHC 1类效果的A链、B链和膜结合的IL-15在IFN-DC调节NK细胞激活和提前IFN-γ产生中的关键作用. 整个结果表明 IFN-DC利用负载自体凋亡 FL细胞促进CD8(+) T细胞抗癌，是一个有价值的免疫治疗办法。(自然杀伤细胞( nature killer cell , NK 细胞) 是淋巴细胞的一个亚群，约占外周血淋巴细胞的10% -15% 。常用的人NK 细胞的表型标志是CD56 + 、CD16 + 、CD 19-、CD3-，既不表达T 细胞的表型(TCRαβ或TCRδγ 或CD3)，又不表达B 细胞的表型( CD 19或BCR 受体)。NK 细胞由造血干细胞发育分化而来，包括NK祖细胞(progenitor NK cell, pNK) 、NK 细胞前体细胞(NK precursor , NKp) 、不成熟N K 细胞( immature NK cell , iNK )和成熟NK 细胞(NK) 的不同分化阶段，各种过渡型NK 细胞和成熟NK 细胞具备各自特有的表型标志，可根据需要向各类器官或组织迁移并进一步成熟分化。根据人类N K 细胞表达CD56 分子的表面密度可将NK 细胞分为CD56bright和 CD56dim二个亚群。CD56dimNK亚群占外周血NK 细胞的90% ，为终末分化的NK 细胞亚群，以杀伤功能为主; CD56dim高表达趋白化因子CXCR1 、CX3CR1 以及ChemR23 受体，提示能够趋化招募至外周炎症部位。CD56brightNK 细胞亚群占外周血NK 细胞的10 % ，为中间期过度分化的NK 细胞亚群， 具备对细胞因子的增殖应答能力，以分泌细胞因子为主; CD56bright NK 细胞亚群优势表达CD62L 、CCR7 、CXCR4 以及一系列黏附分子，提示该群细胞易于在次级淋巴组织及非淋巴组织中聚集;CD3ζ 信号接头分子在CD56brightNK细胞的表达水平明显低于CD56dimNK细胞，可能是其杀伤功能存在差异的原因。NK细胞识别靶细胞是MHC非限制性的，主要识别靶细胞MHC 1 类抗原，这种识别对NK 细胞杀伤活性产生抑制信号，从而避免N K 细胞对"自己"的攻击;肿瘤细胞因为可以丢失MHC1 类抗原而无法传递抑制信号，从而导致NK 细胞活化并诱发杀伤作用，这是最早期的NK 识别假说一"丢失自我"学说。NK细胞抑制型受体包括多种识别MHC 1类分子的特异性受体，人类NK细胞抑制型受体主要有"杀伤免疫球蛋白样受体( KIR ) "家族和C型凝集素样受体家族( CD94/ NKG2A-B , CD94/NKG2C-E) 。NK 细胞的杀伤功能是细胞释放的杀伤介质穿孔素和颗粒酶使靶细胞凋亡，该过程需要NK细胞识别受体与靶细胞的直接接触方可实现， CD56dimNK细胞亚群主要借此方式杀伤靶细胞; NK细胞可以通过膜TNF家族分子( FasL 、TRIAL 、mTNF等)与靶细胞膜配体结合诱导靶细胞凋亡，该过程不需要NK 细胞识别受体与靶细胞的直接接触， CD56brightNK细胞亚群可借此方式杀伤靶细胞。NK 细胞还可以通过抗肿瘤抗体IgG1 和IgG3 作为桥梁，其Fab 端特异性识别肿瘤， Fc段与NK细胞FcRγ4a 结合，产生抗体依赖的细胞介导的细胞毒作用(ADCC) 。NK 细胞的组织分布.NK细胞比例以肺>肝脏>外周血>脾脏>骨髓>淋巴结>胸腺的顺序分布，总数则以脾脏>肺>骨髓>外周血>淋巴结>肝脏>胸腺的顺序分布。 人类成熟NK 细胞中CD56dimNK细胞亚群主要分布在外周血，占NK 细胞总数的90 % ，以杀伤功能为主CD56brightNK亚群在外周血仅占NK 细胞总数的1 0 % ，但是在淋巴结可占NK细胞总数的近100 %，在肿痛组织边缘、肺结核胸腔积液、肠道、子宫等天然免疫第一线或免疫应答场所中CD56brightNK 亚群的比例也明显高于CD56dimNK细胞亚群，引起免疫学家们研究CD56brightNK的极大兴趣。小鼠NK 细胞表面表达大量L-选择素和选择素糖蛋白配体-1 (PSGL-1) 。已知L-选择素对NK细胞迁移至淋巴结中至关重要。人类NK 细胞中CD56brightNK亚群大量表达L-选择素，提示该细胞有穿越血管内皮细胞迁移至组织的能力。CD56dimNK细胞不表达L-选择素，NK细胞中LEA-1也很关键，是穿越血管内皮的重要分子。人类N K 细胞向上皮细胞迁移可依赖于CCR2、CCR5 、CXCR3 或者ChemR23 ， 小鼠NK 细胞向肝脏迁移则依赖于CCR2 和CCR5 。NK 细胞各亚群表面趋化因子受体表达是特异的。CDl l b hi CD27 hi NK细胞组成性表达CXCR3 , CDl l b hi CD27 lo细胞则不表达CXCR3 。 两群NK 细胞亚群都显示出广谱的CXCR4 表达，但是都不表达CCR5 和CCR7。与CDl l b hi CD27loNK 相比， CDl l b hi CD27 hi NK 细胞对于CXCR3 配体(IP-10， I-TAC ) 、CXCR4 配体都显示出较强的趋化活性。近年研究证实N K 细胞表达多种受体实现自我识别调控。已经证明NK 细胞受体( NK receptor ,NKR)有数十种之多。从功能角度可分为两大类受体: 能够激发NK细胞杀伤作用的活化受体(activaling receptor)和能够仰制NK细胞杀伤作用的抑制受体( inhibitory receptor ) ;从蛋白结构角度分为两大家族; 一类为C 型凝集素样受体，称为杀伤凝集素样受体( killer lectine-like receptor， KLR ) ，另一类受体为免疫球蛋白样杀伤受体( killer immunoglobulin-likereceptor， KIR )。1 986 年Karre等发现的" Missing-Self " 现象是NK细胞识别机制的开山之作。2006 年Yokoyama和Raulet 分别提出的" Licensing" 假说和" Disarming" 模型，大大扩展了对NK 细胞的识别机制的认识，认识到NK细胞抑制性信号与活化性信号之间的平衡决定NK细胞与靶细胞相互作用的结果。正常情况下，靶细胞表面自身MHC1类分子通过与NK细胞表面抑制性受体结合而传导抑制性信，以抑制NK细胞活化。感染等细胞应激状态下MHC 1 可丢失，这种平衡被打破，NK细胞即可能对靶细胞行使杀伤效应。目前NK 细胞的天然免疫识别机制可以扩展为" Nonself" 、”Missin g-Self" 、" Induced Self" 三类识别模式，基本可以囊括NK 细胞识别活化的各种情况。NK 细胞受体直接识别非己成分(Ly49H与MCMV 感染的细胞表达的病毒蛋白m157结合) ，从而激活KARAP/DAP12 信号通路， 此种识别为" Nonself" 模式; 当感染或肿瘤发生时靶细胞表面自身MHC1 类分子水平下调，导致抑制性信号减弱， 诱导NK细胞活化，此种识别为" Missing -Self" 模式;在感染、肿瘤等情况下靶细胞上调活化性受体(如NKG2D ) 的配体分子MICA/ ß 、Raels 、H60 、ULBP 等的表达，可激活KARAP/ DAP12或DAP10信号通路，此时活化性信号"战胜"抑制性信号，从而诱导NK 细胞活化，称为"lnduced Self""识别模式。近期研究表明， NK细胞具有获得性免疫细胞的关键特征一一免疫记忆功能。记忆性NK细胞主要来自于肝脏， 该亚群主要集中于Thy-1 、Ly49C-1 + NK 细胞中， 其比例仅占肝脏NK细胞的10 % 。记忆性NK 细胞迁移并定位于肝脏与自身表达CXCR6 受体密切相关。肝脏NK细胞中35% - 55 %为CXCR6+，脾脏NK细胞中仅仅3% -5%为CXCR6 + 。NK 细胞细胞具有强大的细胞因子分泌功能。可以大量产生IFN-γ，是机体TFN-γ的主要来源。NK 细胞大量产生TNF-α 、GM-CSF 、IL- 10、IL-22 等细胞因子， 也是特定环境下主要的产生细胞。K 细胞被称为连接天然免疫和获得性免疫的桥梁。研究NK 细胞对获得性免疫应答的调控作用极大拓展了对NK 的认识。NK 细胞对其他免疫细胞，如巨噬细胞、树突状细胞以及细胞毒T 细胞的功能均具有调节作用。NK 细胞分泌的I FN-γ 能够促进巨瞌细胞的活化和维持Th1 的优势状态。NK 细胞对DC 细胞的调控作用被认为是NK 调节获得性免疫的基础，大量实验证实N K 一方面可以通过分泌TNFa 和IFNγ 促进DC 表达共剌激分子与MHC 分子，进而语使单核细胞转变为成熟DC 细胞，并通过杀伤靶细胞提供抗原以供DC 加工递呈· 另一方面NK 细胞也可以通过Kp30 、NK p46 等活化受体杀伤未成熟DC 细胞，进而发挥免疫抑制作用，而成熟DC 细胞通过高表达MHI 类分子免受杀伤。NK 细胞对获得性免疫应答的调节还表现在对T细胞的直接作用中， 经典观点认为NK 通过分泌LFN -y促进Th l 细胞极化，然而近期研究却表明NK 细胞在病毒感染、自身免疫病及移植排斥中都发挥着重要的限制T细胞应答的功能。NK细胞在白血病的免疫治疗已展现良好的应用前景。供者NK细胞通过"missing-self" 模式可以有效地杀伤受者残留的白血病细胞，抑制疾病复发。阻断抑制性受体KIR与MHC1类分子结合而逆转NK细胞耗竭( exhaustion)的抗体已进入2期l临床试验，阻断KIR后自体的NK细胞可以有效杀伤白血病细胞。在HBV慢性感染的病人中、NK细胞的活性受到了明显的抑制，阻断抑制性受配体NKG2A可以恢复NK细胞清除HBV功能，说明疾病状态下的人NK细胞特性会发生改变。，如已获临床批准的单抗药物利妥昔( rituximab ) 治疗效果便可能依赖于其Fc 段对NK 细胞的导向杀伤功能。由于人的个体差异性很大，人NK 细胞基础研究较薄弱，人NK 细胞的临床应用还没有达到理想效果。欲利用NK 细胞进行疾病的免疫治疗，仍需对人NK 细胞的基础生物学特性和临床疾病中NK 细胞特性进行大量细致的研究。)(抗原提呈细胞( antigen-presenting cell，APC) 是指能摄取和在细胞内加工处理抗原，并将抗原信息提呈给T淋巴细胞的细胞。通常所指的抗原提呈细胞包括树突状细胞( dendritic cel1, DC ) 、巨噬细胞( macrophage ，Mψ) 、B 淋巴细胞等能表达MHC II 类分子的细胞，也将其称为专职性抗原提呈细胞(professional APC) 。然而，机体的有核细胞均表达MHC1类分子，它们可将细胞内的蛋白质抗原(内源性抗原， endogenous antigen) 加工处理成为抗原肽，并以抗原肽-MHC 1 类分子复合物的形式将抗原信息提呈给CD8+ 的杀伤性T细胞( cytotoxic T cell , CTL) ，成为CTL杀伤的靶细胞。通常并不将该类有核细胞称为APC ，只称为靶细胞。但有人仍广义地定义APC为: 能加工处理抗原并以抗原肽-MHC分子复合物的形式提呈抗原信息的所有细胞。除了专职性抗原提呈细胞之外，内皮细胞、成纤维细胞、上皮及间皮细胞等也能加工、处理和提呈抗原，但其能力较弱，统称为非专职抗原提呈细胞。1973 年， Steinman 和Cohn 在小鼠脾脏中发现具有树枝状突起的独特形态的细胞，并将之命名为树突状细胞。DC是目前所知抗原提呈功能最强的APC，最大的特点是能够剌激初始型T细胞(naive T cell ) 活化和增殖，而Mψ 、B 细胞等仅能剌激已活化的T细胞或记忆性T细胞，因此， DC 是特异性免疫应答的始动者。随着对不同组织来源DC 研究的深入，目前已知的DC的亚群包括存在于淋巴组织、血液和非淋巴组织的经典DC (conventional DC , cDC )和分泌I型干扰素的浆细胞样DC ( plasmacytoid DC , pDC) 。其中，经典DC 的主要功能是诱导针对入侵抗原的特异性免疫应答并维持自身耐受，而pDC的主要功能则是针对微生物，特别是病毒感染产生大量的I 型干扰素并激活相应的T细胞。)http://www.ncbi.nlm.nih.gov/pubmed/27356950Gene Ther. 2016 Jun 30. doi: 10.1038/gt.2016.48.Adual chain chimeric antigen receptor (CAR) in the native antibody format fortargeting immune cells towards cancer cells without the need of an scFv.文中提出一个双链CAR免疫治疗拓宽了单链CAR（scFv）治疗所具有的局限性。http://www.ncbi.nlm.nih.gov/pubmed/27355489JAMA Oncol. 2016 Jun 23. doi: 10.1001/jamaoncol.2016.1061.Variationin the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in BreastCancer Subtypes: A Systematic Review.本回顾包括 13 914位乳腺癌患者. 平均11% (5%-26%)主导肿瘤浸润的淋巴细胞（TIL）, 约16%患者无TIL. 三阴乳腺癌患者更高的TIL发生率(20%; 4%-37%). 与her2+和荷尔蒙受体阳性（HR+）或HR-/HER2+ 约16% (11%-24%)相当. HER2- (HR+)最低TIL发生率6% (3%-12%). CD8+ T细胞浸润表示I型免疫出现在约48%的患者(32%-80%) 与三阴乳腺癌 (60%; 40%-91%) 和HER2+ (61%; 40%-83%)差不多.很少HR+ 肿瘤显示 CD8+ TIL (43%; 30%-73%). 最高水平的FOXP3+ 细胞在三阴乳腺癌 (70%; 65%-76%) 和HER2+ (67%; 61%-74%)观察到. 少数HR+ 患者显示高水平的肿瘤浸润的FOXP3+细胞 (38%; 35%-41%).可见TIL在乳腺癌中的重要性。淋巴细胞水平与乳腺癌免疫治疗的关系密切效果，值得关注。（Foxp3是控制Treg细胞发育和功能的关键转录因子之一，它的发现是Treg免疫生物学重要的进步，为人们进一步了解Treg功能和作用机制打开了一扇“门”。虽然人们也发现Treg发育和功能也需要其他转录因子如AhR和STAT5的参与，但是Foxp3仍旧是Treg细胞系的主要调节因子。实验表明，在体外或体内诱导初始T细胞表达FoxP3后可以出现Treg样的免疫抑制作用，表明Foxp3是控制免疫抑制分子表达的关键因素；因此，阐明Foxp3的分子靶点是透彻理解Treg免疫抑制作用的必要条件之一。）http://www.ncbi.nlm.nih.gov/pubmed/27354645AnticancerRes. 2016 Jul;36(7):3715-24.ImmunohistochemicalAnalysis of WT1 Antigen Expression in Various Solid Cancer Cells.DC疫苗治疗效果不错离不开癌症细胞中靶蛋白表达。肾母细胞瘤基因（Wilms' tumor 1，WT1)已被确定为癌症免疫治疗的一个分子靶点。我们通过各种癌症细胞评估 WT1、黏蛋白（mucin 1 ，MUC1）、主要组织相容性复合体1类分子 （major histocompatibility complex ，MHC)表达状况.取自738位同意接受免疫治疗后患者组织样品， WT1染色在25.3%患者组织观察到，只有8.5%表现中到高强度表达； 此外, WT1倾向存在于细胞核或细胞质。抗MHCl 单抗的肿瘤阳性染色在98.6%的患者组织观察到，抗MUC1单抗肿瘤阳性染色观察到76.8%. 本研究说明 MUC1- and WT1治疗的临床意义.(主要组织相容性复合体( major histocompatibility complex，MHC) 是所有生物相容复合体抗原的一种统称(MHC molecule)，表示由MHC 基因家族（MHC classⅠ,class Ⅱ,class Ⅲ）编码而成的分子，位于细胞表面，主要功能是绑定由病原体衍生的肽链，在细胞表面显示出病原体，以便于T-细胞的识别并执行一系列免疫功能（例如杀死已被病菌感染的细胞，激活巨噬细胞杀死体细胞内细菌，激活B细胞产生抗体等。现已证明，MHC不仅控制着同种移植排斥反应，更重要的是与机体免疫应答、免疫调节及某些病理状态的产生均密切相关。不同种类哺乳动物MHC基因的编码产物的名称各异。人类的MHC通常被称为HLA (human leucocyte antigen，HLA)， 即人类白细胞抗原。MHC基因（MHC gene），定位于人类第六号染色体短臂，呈高度多态性。其编码的分子表达于不同细胞表面，参与抗原提呈，制约细胞间相互识别及诱导免疫应答。小鼠的MHC称为H-2复合体。)http://www.ncbi.nlm.nih.gov/pubmed/27354469Clin Cancer Res. 2016 Jun 27. pii: clincanres.0040.2016.CTLA-4limits anti-CD20-mediated tumor regression.CTLA-4信号通路阻塞并导致抗CD20的免疫治疗失败。（细胞毒T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen-4, CTLA-4）又名CD152，是一种白细胞分化抗原，是T细胞上的一种跨膜受体，与CD28共同享有B7分子配体，而CTLA-4与B7分子结合后诱导T细胞无反应性，参与免疫反应的负调节。基因重组的CTLA-4 Ig可在体内外有效、特异地抑制细胞和体液免疫反应，对移植排斥反应及各种自身免疫性疾病有显著的治疗作用，毒副作用极低，是目前被认为较有希望的新的免疫抑制药物。）http://www.ncbi.nlm.nih.gov/pubmed/2735416ScandJ Immunol. 2016 Jun 29. doi: 10.1111/sji.12456. Therapeuticvaccination against a modified minimal survivin epitope induces functional CD4T-cells that recognize survivin-expressing cells.生存素survivin对肿瘤细胞生存至关重要且在很多肿瘤分布，是一个合适的免疫治疗靶点。http://www.ncbi.nlm.nih.gov/pubmed/27350884Clin Transl Immunology. 2016 May 20;5(5):e85. doi:10.1038/cti.2016.22. eCollection 2016.Toll-likereceptors: the swiss army knife of immunity and vaccine development.内在免疫细胞在预防感染和疾病起关键作用。免疫细胞的核心功能是其广泛的特异性，包括通过模式识别受体(PRR)探查病理相关的模式和损伤相关模式。几个PRR家族成员已被确认，包括：TOLL样受体（Toll-like receptors，TLR), C型凝聚素样受体（C-type lectin-like receptors, CLR）,维甲酸诱导受体（retinoic acid-inducible gene-like receptors，CLR）, 核苷酸结合寡聚体域样受体（nucleotide-binding oligomerizationdomain-like receptors）. TLR是PRR家族研究最多的一个成员。 与抗原提呈细胞(APC)的TLR结合配体主要是DC, DC诱导APC成熟, 诱导炎性细胞因子，诱导幼稚T细胞获得免疫力。因此，激活TLR既促进内在炎性反应又诱导适应的免疫力。因此，20多年的众多研究证明TLR活性与免疫性疾病及癌症存在密不可分的联系。TLR信号治疗性免疫治疗可加速和增强特异性疫苗应答，或使用靶向TLR小分子抑制剂治疗疾病.据此，TLR可以看做免疫系统的一把瑞士军刀。http://www.ncbi.nlm.nih.gov/pubmed/27350335Nature. 2016 Jun 27. doi: 10.1038/nature18945.Neoantigenlandscape dynamics during human melanoma-T cell interactions.造成DNA损失的新生抗原的识别成为癌症免疫治疗的主要驱动力量。如T细胞检查点阻滞和过继T细胞治疗。因此，选择性增强T细胞抗基因上明确的新生抗原战略正在不断研究开发中。在老鼠模型中， T细胞的压力使肿瘤形成新抗原导致原治疗针对的抗原消失。不过，目前尚不知道是否T细胞识别的人类癌症抗原随着时间变化不断变化着。本文分析2例4期黑色素瘤患者使用过继T细胞治疗的新抗原的稳定性， 原T细胞识别的新抗原选择性丢失，或降低表达或突变等位基因丢失。 值得注意的是，T细胞识别的抗原丢失伴随现T细胞无特异性的新抗原的产生。说明癌T细胞相互作用的动态性，建议使用T细胞特异性抗原的免疫治疗扩大特异性抗原的范围，以避免治疗耐药。http://www.ncbi.nlm.nih.gov/pubmed/27350283Cancer Med. 2016 Jun 28. doi: 10.1002/cam4.800. Novelrole of ASC as a regulator of metastatic phenotype.细胞骨架的重构和信号转导的混乱常常与癌症进展有关。尤其是包含caspase招募域的凋亡相关颗粒样蛋白 (ASC) 已被报告过是一个促凋亡分子在几种癌症里保持静默。ASC是一个良好表征的接头蛋白涉及多蛋白寡聚体形成，称为炎症小体，在激活和分泌天然免疫细胞IL-1β and IL-18起关键性作用。 为研究ASC在癌症中的作用，使用体内体外敲除ASC老鼠模型， ASC敲除提升 B16BL6黑色素瘤癌细胞的活动能力和增强癌细胞侵袭能力，侵袭伪足的形成及Src磷酸化水平显著提升。 由于caspase-8已被报告过通过其Tyr380磷酸化增强细胞的迁移能力，并在ASC敲除的细胞中升高但被z-VAD-fmk or z-IETD-fmk削弱. 而且, 老鼠静脉注射ASC缺失B16BL6细胞增加肺转移。 表明ASC通过细胞骨架重构建模和Src-caspase-8信号通路抑制癌症的进展和转移。 http://www.ncbi.nlm.nih.gov/pubmed/27350082JInorg Biochem. 2016 Jun 16. pii: S0162-0134(16)30184-2. doi:10.1016/j.jinorgbio.2016.06.021. Anticancermetal drugs and immunogenic cell death.抗癌的化学治疗和免疫应答之间的相互作用就是所谓的免疫产生的细胞死亡（immunogenic cell death，ICD). ICD被发现是疫苗致癌细胞死亡因疫苗使用前使用过化疗，称之为ICD诱导剂。在同种移植老鼠模型中，只有小部分药物能够触发ICD但并不清楚与药物的化学结构或原活性模型的关系。然而，活性氧簇（reactive oxygen species ，ROS)生成和内质网构造（ endoplasmic reticulum ，ER)应急的诱导明显与ICD相联系. 考虑到金属药物，奥沙利铂不是顺铂被认为是一个可靠的ICD诱导剂。 因此，抗癌金属药物值得关注。http://www.ncbi.nlm.nih.gov/pubmed/27349980Immunotherapy. 2016 Jun;8(7):809-19. doi:10.2217/imt-2016-0001.Immunecheckpoint blockade in human cancer therapy: lung cancer and hematologicmalignancies.肿瘤免疫逃逸是癌症的一个主要特征，免疫检查点(PD-L1, PD-L2, B7-H3, B7x and HHLA2) B7家族的表达是免疫逃逸的机制，通过此机制肿瘤抑制T细胞功能。阻滞B7-1/B7-2/CTLA-4 和 PD-L1/PD-L2/PD-1相互关系的抗体取得惊人的临床成功，与传统化疗相比低毒。 即使只有小部分人应答于治疗，这些患者由于免疫记忆其生存时间跨度显著比其他药物治疗更长。（免疫检查点( immune checkpoint) 是随着近年对肿瘤微环境和肿瘤免疫逃逸机制的深入研究，发现的一组介导免疫调节的重要分子，如负性B7 家族分子: PD-L1 (B7-Hl )/PD-l 、B7-H3 、B7-H4 和CTLA-4 以及Tim-3 等。它们是免疫系统维持自身耐受和机体稳态、避免组织损伤和调节适度的免疫应答的重要抑制性分子，也是机体免疫系统在长期进化过程逐步建立的调节机制，在免疫应答的适时中止中发挥极为重要的作用。在肿瘤微环境诱导下，肿瘤细胞异常表达一系列负性共刺激分子，构成独特的免疫逃逸的微环境，抵抗机体内在的抗肿瘤免疫，尤其是抑制肿瘤抗原特异性T 细胞，成为肿瘤免疫逃逸的主要机制。由于许多免疫检查点分子需要与配体/受体结合后才能活化，所以可以用抗体阻断或利用重组蛋白调控其信号途径，使肿瘤组织微环境重新获得抗肿瘤的免疫力。鉴此，抗免疫检查点CTLA- 4、PD-1及PD-L1单抗在多种肿瘤治疗中显示出的卓著疗效，使阻断免疫卡控点策略在肿瘤免疫治疗中的前景受到空前关注，其中涉及的机制和关键分子也将为肿瘤免疫治疗提供新的途径。）http://www.ncbi.nlm.nih.gov/pubmed/27349385J Exp Clin Cancer Res. 2016 Jun 27;35(1):103. doi:10.1186/s13046-016-0375-2.TargetingmicroRNAs as key modulators of tumor immune response.肿瘤微环境包含不同类型的免疫细胞，它们共同调节抗瘤与促瘤信号精细平衡。据此, 癌症与免疫细胞之间的交流机制需要广泛说明。microRNAs (miRNAs) 已表明在生理和病理状况起关键的免疫应答调节作用。特别是, 不同的miRNAs已被报告过在控制与肿瘤相关免疫细胞发展和功能起不同作用。本回顾针对最重要的miRNAs在不同实体瘤环境下成为免疫应答的关键调节者。最近一些研究表明肿瘤微环境存在miRNA介导机制调节肿瘤相关免疫细胞的招募和激活。而且，多种 miRNAs 已被发现靶向与癌症相关的关键免疫通路，且通过癌症或免疫细胞调节免疫抑制因子或免疫刺激因子的分泌。miRNA交换形式和基于miRNA的递送战略也被探讨过。据此，调节单个或多个miRNAs 有可能增强或抑制特定免疫群体，以支持抗瘤的免疫应答，有助于负影响肿瘤生成。可能开发新的基于miRNA癌症治疗战略以更有效免疫介入治疗。http://www.ncbi.nlm.nih.gov/pubmed/27349304Hum Pathol. 2016 Jun 24. pii: S0046-8177(16)30129-0.doi: 10.1016/j.humpath.2016.06.011. B7-H4Expression in Ovarian Serous Carcinoma: A Study of 306 Cases.免疫共刺激配体B7家族是一组细胞表面蛋白，结合于淋巴细胞表面受体精确调节免疫应答。 这些蛋白的异常表达对肿瘤免疫逃逸起关键作用。靶向B7家族某些成员的免疫治疗包括PD-L1非常有效抑制肿瘤生长。不过，目前还不知道为什么治疗只有小部分人有效？ 本文假设其他B7家族成员单独或一起及PD-1在肿瘤病理生成和进展起关键性作用。本文通过306例卵巢浆样癌研究一个新发现 B7家族成员B7-H4是否验证假设。91% (267/293) 高级卵巢浆样癌和69% (9/13) 低级癌表达 B7-H4，其表达的差异具有明显的统计学意义(P=.002). B7-H4蛋白表达在高级卵巢浆样癌与肿瘤分期有关(P<.01)，与OS或DFS无关。B7-H4频繁表达于卵巢浆样癌尤其是高级卵巢浆样癌，表示其为新的免疫治疗靶点。http://www.ncbi.nlm.nih.gov/pubmed/27344341CancerImmunol Immunother. 2016 Jun 25. Modulationof innate immunity in the tumor microenvironment.本文认为检查点抑制剂有效群体很少的原因在肿瘤微环境(TME)的免疫抑制，研究TME以便设计合适的治疗策略。本文研究TME中那些与生俱来的免疫细胞包括DC、NK细胞，发现分泌自肿瘤和基质的金属基质蛋白酶（matrix metalloproteinase-2 ，MMP-2)快速避开IFNAR1抗体刺激TME 中DC细胞的TLR-2 蛋白，TLR-2编码DC细胞促进促肿瘤生成的TH2 细胞分化。此外， NK细胞在黑色素瘤患者功能性耗竭， 确认Tim-3表达是主要原因，抗Tim3抗体可部分逆转。 采用局部介入战略如在肿瘤内使用DC激活的Poly-ICLC，并进行比较不同的TLR拮抗剂和黑色素瘤抗原联合肿瘤疫苗临床一期实验。http://www.ncbi.nlm.nih.gov/pubmed/27343548Oncotarget. 2016 Jun 13. doi:10.18632/oncotarget.9915. Combinationof radiotherapy and vaccination overcome checkpoint blockade resistance.胰腺癌患者单独使用疫苗或检查点抗体或放疗效果不好，联合使用取得不错效果http://www.ncbi.nlm.nih.gov/pubmed/27342591CancerImmunol Immunother. 2016 Aug;65(8):983-94. doi:10.1007/s00262-016-1861-2. Epub 2016 Jun 24.Circulatingimmune cell phenotype can predict the outcome of lenalidomide plus low-dosedexamethasone treatment in patients with refractory/relapsed multiple myeloma.本文通过来那度胺联合低剂量地塞米松(Len-dex)治疗难治或复发的多发骨髓瘤，研究外周血免疫细胞数与治疗效果关系。通过3个周期治疗外周血CD3(+)细胞、CD4(+)细胞、CD8(+)细胞出现率明显下降，而NK细胞出现率明显升高。对于髓源抑制细胞（myeloid-derived suppressor cell，MDSC) 亚群, MDSC粒细胞出现率在一期治疗后瞬间增加，第一期和第三期治疗后单核MDSC （monocytic MDSC，M-MDSC)细胞增加。81个评估患者中，三期Len-dex治疗后CD8(+) 细胞下降和M-MDSC增加的患者没能获得很好的部分应答. 治疗前高比例的NKT样细胞(CD3(+)/CD56(+)) 预示更长的TTP.患者在三期治疗后CD3(+) 细胞和 CD8(+)细胞水平更少的下降显示到下一次治疗的时间更长。外周血免疫细胞的变化对多发骨髓瘤的治疗是有意义的。（MDSC 髓源抑制性细胞(myeloid derived suppressor cell , MDSC) 在肿瘤、细菌或寄生虫感染、脓毒血症、骨髓移植、自身免疫性疾病等病理状态下，会大量产生和累积，抑制机体免疫系统。 ILT2转基因小鼠研究发现， HLA -G/ ILT2相互作用直接诱发机体外周血CD11b +Grl + MDSC 细胞增殖，使IL-4 、lL-13 分泌水平上调，延长同种异体移植物存活时间. HLA-G 抗原诱导生成的MDSC 细胞并通过细胞因子调节Thl/Th2/ThI7 细胞间的平衡，使平衡移向Th2 型免疫应答，促进肿瘤的发生发展。值得一提的是， MDSC 细胞在肿瘤中异常过表达，大量的MDSC 细胞能抑制效应性T 细胞和成熟型OC 的免疫活性，井剌激抑制性T细胞产生，导致肿瘤细胞逃避机体的免疫监视。）http://www.ncbi.nlm.nih.gov/pubmed/27341020Oncotarget. 2016 Jun 21. doi:10.18632/oncotarget.10190. Definitiveactivation of endogenous antitumor immunity by repetitive cycles ofcyclophosphamide with interspersed Toll-like receptor agonists.许多癌症具有招募和收买天然抗癌免疫细胞。不过，免疫抑制在一些癌症的亚群通过治疗被逆转，如检查点抑制剂、TOLL样受体拮抗剂（Toll-like receptor agonists，TLRa). 而且, 化疗杀伤白细胞对人体免疫产生抑制，包括髓源抑制细胞（myeloid-derived suppressor cells ，MDSCs) 和调节性T细胞（regulatory T-cells ，Tregs). 本文假设化疗产生的白细胞减少可能带来免疫潜能通过共同调节TLRa模仿因化疗引起危险生命的感染. CpG (ODN 1826)或CpG+poly(I:C) 与环磷酰胺 （cyclophosphamide，CY) 联合治疗产生独特耐受良好协同效果，持久根除晚期老鼠肿瘤，包括 4T1 (乳腺癌breast), Panc02 (胰腺癌pancreas) and CT26 (结直肠癌colorectal). 最佳治疗需要天然CD8+ and CD4+ IFNγ产生的 T细胞. 肿瘤特异性的IFNγ产生T细胞在CY诱导的白细胞减少期间持续保留。 然而调节性T细胞Tregs被持续消灭，尤其是肿瘤内。 片段相关MDSCs被CY+TLRa联合治疗周期性消灭，残留的单核MDSCs只需要持续暴露于CpG 或CpG+IFNγ以有效攻击恶性细胞而不伤害正常细胞。尽管治疗上调肿瘤程序性死亡配体（Programmed Death Ligand-1,PD-L1），肿瘤细胞死亡还是出现，不过PD-L1能被磷酸盐脂质体消灭吞噬细胞或一氧化氮合成酶抑制剂阻滞。 Naive老鼠模型CY+TLRa也诱导肿瘤致死的髓细胞，表示CY+TLRa的免疫调节的影响出现在完全不荷瘤老鼠身上，肿瘤诱导的MDSCs 不是肿瘤致死髓细胞的前驱细胞的主要来源。重复CY+TLRa 治疗能够调节天然免疫力消灭晚期肿瘤，无需疫苗或过继T细胞治疗。人体血液单核细胞通过体外TLRa+IFNγ激活也具有相似的肿瘤致死能力，表明本研究具有潜在有意义治疗价值，可以从老鼠模型转移到到人体治疗研究。（2016年7月14日 讯 /生物谷BIOON/ --近日，刊登于国际杂志Oncotarget上的一项研究论文中，来自梅奥诊所的研究人员通过研究开发了一种新型药物组合，可以增强机体免疫系统精确狙击杀灭癌细胞的能力，这种新型药物组合或许可以在治疗小鼠机体恶性癌症及转移性癌症上具有一定的治疗效应。研究者Peter Cohen博士表示，在引发大问题前癌细胞通常会在机体中潜伏数月时间，在这期间其通常会使得免疫系统与癌症共存；文章中我们以Toll样受体（TLR）激动剂来模拟侵入性的细菌，检测其“诱骗”免疫系统攻击癌症的能力，由于化疗方法可以增强免疫疗法，随后我们利用10种不同的化疗制剂对成对的TLR激动剂进行了筛查。文章中，研究者对携带高度恶性乳腺癌（4T1）和胰腺癌（Panc02）的小鼠模型进行靶向研究，他们发现，当化疗制剂环磷酰胺同TLR激动剂进行结合时，恶性的4T1 和Panc02癌症就会在两轮疗法后发生大范围的退化；如果小鼠完成了另外5轮巩固性的疗法那么其癌症病情便不会复发，仅仅当TLR激动剂同环磷酰胺结合时才会持久性地根除癌症，而且目前并没有其它化疗制剂的效果可以达到环磷酰胺的效果。研究者还发现，这种结合性药物疗法耐受性较好，相比单独使用TLR激动剂或环磷酰胺而言毒性作用较小。研究者表示，患癌小鼠机体中的T淋巴细胞免疫反应可以抵御肿瘤，当每周注射TLR激动剂或环磷酰胺疗法后就可以有效抑制小鼠机体癌症的发展，更重要的是，这种疗法制剂并不需要直接注射到肿瘤中，同时其还可以高效抵御肿瘤的转移。如今梅奥诊所的研究者还在继续深入研究，进行FDA批准的临床试验来检测是否恶性癌症患者对这种组合性疗法的反应同患癌小鼠一样。（生物谷Bioon.com））http://www.ncbi.nlm.nih.gov/pubmed/27339708NatRev Cancer. 2016 Jul;16(7):447-62. doi: 10.1038/nrc.2016.54.Therole of myeloid cells in cancer therapies.与T淋巴细胞相比，与癌症相关骨髓细胞更少受到关注，但由于髓细胞与患者的生存有关引起研究者突变关注。髓细胞调节肿瘤相关的关键行为，如免疫逃逸以及实际上影响所有癌症的治疗。靶向髓细胞可以弥补当前治疗的局限性。http://www.ncbi.nlm.nih.gov/pubmed/27333363PigmentCell Melanoma Res. 2016 Jun 22. doi: 10.1111/pcmr.12503. ResidualFDG-PET metabolic activity in metastatic melanoma patients with prolongedresponse to anti-PD-1 therapy.27位无法手术的IIIC or IV 期黑色素瘤长期使用PD-1抗体治疗，然后进行FDG-PET(PET/CT) 扫描以验证患者长期治疗带来代谢性灭活损伤。第一次开始治疗后平均15.2 月 (12-29 月)， 15/27 (56%) 有阳性结果. 其中8位还经过活检; 5/8 (62%) 黑色素瘤，3/8 (38%) 免疫细胞浸润. 扫描结果阴性的12位患者, 6 为有残留可见损伤, 5位停止治疗，随后6到10个月无人复发。 经过PD-1治疗有残留转移灶患者在很长时间没有复发可能是代谢性灭活损伤，原因应该是肿瘤免疫细胞浸润而非黑色素瘤本身。http://www.ncbi.nlm.nih.gov/pubmed/27332773Braz J Med Biol Res. 2016 Jun 20;49(7). pii:S0100-879X2016000700701. doi:10.1590/1414-431X20165263.Effectsof lung cancer cell-associated B7-H1 on T-cell proliferation in vitro and invivo.B7同源1（B7 homolog 1 ，B7-H1) 是最有免疫抑制潜能的B7家族分子。本文研究肺癌与肿瘤相关B7-H1对T细胞增殖效果. 使用人腺癌A549和老鼠Lewis 肺癌(LLC) 进行抗B7-H1抗体研究， 体外实验 T与A549 一起培养，癌细胞明显抑制T细胞的增殖，而增加抗B7-H1抗体戏剧性逆转T细胞增殖被抑制状况。老鼠模型也产生类似效果，抗B7-H1抗体显著降低肿瘤生长。肿瘤相关B7-H1抑制T细胞增殖便于免疫逃逸，为有希望的癌症免疫治疗靶点。----------------------------------------------------------------------------------------------------------------------------http://www.ncbi.nlm.nih.gov/pubmed/27323411Oncotarget. 2016Jun 13. doi: 10.18632/oncotarget.9980. Fas ligand and lytic granule differentiallycontrol cytotoxic dynamics of Natural Killer cell against cancer target.NK细胞与癌症靶细胞的相互作用的动态性成为以前研究的主题，但个中限速动力学很少知道。本文研究发现NK细胞被多个细胞毒通路不同的动态控制。发现人类大多数NK细胞，不同NK细胞系杀死肿瘤细胞主要通过溶解颗粒独立的机制进行，特别是通过Fas配体(FasL).FasL和溶解颗粒方式导致有意义的细胞与细胞相互作用的变数。FasL杀死慢，常常需要短暂多个NK细胞的结合逐渐激活caspase-8；而溶解颗粒触发快速细胞毒效应通过类似开关诱导颗粒酶以单个细胞持久结合。而且，白介素2增强2类细胞毒机制通过提升NK细胞靶细胞识别能力和增加NK细胞与癌细胞的相互作用频率。本文研究确认了NK细胞杀死癌细胞的限速的关键所在，也指出非溶解颗粒机制对NK免疫治疗的重要性。.http://www.ncbi.nlm.nih.gov/pubmed/27321181Oncogene. 2016Jun 20. doi: 10.1038/onc.2016.206. Extracellular purines, purinergic receptorsand tumor growth.所有肿瘤细胞以及免疫细胞表达质膜受体为接收胞外核苷 (腺甙) 、核苷酸(ATP, ADP, UTP, UDP and 糖UDP).肿瘤微环境以不寻常的高浓度ATP和腺甙。腺甙是肿瘤免疫抑制环境的主要决定因素。随后由CD39and CD73 催化的ATP水解是肿瘤间质组织主要的腺甙生成通路。胞外ATP和腺甙塑造宿主和肿瘤的应答。 依赖于特定的受体激活，胞外嘌呤介导的宿主这边免疫抑制或免疫刺激，介导肿瘤这边生长刺激或细胞毒性。此领域最近研究进展提供办法解开其中奥秘，为治疗打下基础。 预临床前数据显示靶向腺甙生成通路(即CD73)或腺甙受体(即A2A)减轻免疫抑制和抑制肿瘤生长。另外，试验的肿瘤生长被靶向P2X7（ATP选择性受体）强烈抑制 。本回顾概括了胞外嘌呤/嘌呤信号通路在宿主与肿瘤相互作用所起作用，也强调了一种新的治疗选择。http://www.ncbi.nlm.nih.gov/pubmed/27306805Gan To Kagaku Ryoho. 2016Jun;43(6):678-82..PD-1治疗有效率低的原因有基因突变积累的范围，包括突变负荷，产生新抗原非同义突变，微卫星不稳，成为能够预测免疫治疗是否受益的标志物。http://www.ncbi.nlm.nih.gov/pubmed/27215429Nat Rev Urol. 2016 Jun;13(6):334-52. doi:10.1038/nrurol.2016.84. Epub 2016 May 24.Oncolytic virotherapy for urological cancers.Oncolytic virotherapy is a cancer treatment in whichreplication-competent viruses are used that specifically infect, replicate inand lyse malignant tumour cells, while minimizing harm to normal cells.Anecdotal evidence of the effectiveness of this strategy has existed since thelate nineteenth century, but advances and innovations in biotechnologicalmethods in the 1980s and 1990s led to a renewed interest in this type oftherapy. Multiple clinical trials investigating the use of agents constructedfrom a wide range of viruses have since been performed, and several of theseenrolled patients with urological malignancies. Data from these clinical trialsand from preclinical studies revealed a number of challenges to theeffectiveness of oncolytic virotherapy that have prompted the development offurther sophisticated strategies. Urological cancers have a range of distinctivefeatures, such as specific genetic mutations and cell surface markers, whichenable improving both effectiveness and safety of oncolytic virus treatments.The strategies employed in creating advanced oncolytic agents includealteration of the virus tropism, regulating transcription and translation ofviral genes, combination with chemotherapy, radiotherapy or gene therapy,arming viruses with factors that stimulate the immune response against tumourcells and delivery technologies to ensure that the viral agent reaches itstarget tissue.http://www.ncbi.nlm.nih.gov/pubmed/27222480Blood. 2016 Jul 21;128(3):384-94. doi:10.1182/blood-2015-12-687749. Epub 2016 May 24.Daratumumab depletes CD38+ immune regulatory cells,promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.Daratumumab targets CD38-expressing myeloma cellsthrough a variety of immune-mediated mechanisms (complement-dependentcytotoxicity, antibody-dependent cell-mediated cytotoxicity, andantibody-dependent cellular phagocytosis) and direct apoptosis withcrosslinking. These mechanisms may also target nonplasma cells that expressCD38, which prompted evaluation of daratumumab's effects on CD38-positiveimmune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patientswith relapsed/refractory myeloma from 2 daratumumab monotherapy studies wereanalyzed before and during therapy and at relapse. Regulatory B cells andmyeloid-derived suppressor cells, previously shown to express CD38, wereevaluated for immunosuppressive activity and daratumumab sensitivity in themyeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressingCD38 was identified. These Tregs were more immunosuppressive in vitro thanCD38-negative Tregs and were reduced in daratumumab-treated patients. Inparallel, daratumumab induced robust increases in helper and cytotoxic T-cellabsolute counts. In PB and BM, daratumumab induced significant increases inCD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells whiledecreasing naïve T cells. The majority of patients demonstrated these broadT-cell changes, although patients with a partial response or better showedgreater maximum effector and helper T-cell increases, elevated antiviral andalloreactive functional responses, and significantly greater increases inT-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCRclonality positively correlated with increased CD8(+) PB T-cell counts.Depletion of CD38(+) immunosuppressive cells, which is associated with anincrease in T-helper cells, cytotoxic T cells, T-cell functional response, andTCR clonality, represents possible additional mechanisms of action fordaratumumab and deserves further exploration.（Daratumumab是一种IgG1k抗体，人源化抗CD38单克隆抗体，具有广谱杀伤活性，靶向结合多发性骨髓瘤细胞表面高度表达的跨膜胞外酶CD38分子，可通过多种机制诱导肿瘤细胞的快速死亡。因为健康细胞和所有骨髓瘤细胞均表达CD38，所以用药需要充分考虑药物毒性。）http://www.ncbi.nlm.nih.gov/pubmed/27223090Oncotarget.2016 May 21. doi: 10.18632/oncotarget.9529. Activateddendritic cells delivered in tissue compatible biomatrices induce in-situanti-tumor CTL responses leading to tumor regression.Dendritic cell(DC) based anti-cancer immunotherapy is well tolerated in patients withadvanced cancers. However, the clinical responses seen after adoptive DCtherapy have been suboptimal. Several factors including scarce DC numbers intumors and immunosuppressive tumor microenvironments contribute to theinefficacy of DCs as cellular vaccines. Hence DC based vaccines can benefitfrom novel methods of cell delivery that would prevent the direct exposure ofimmune cells to suppressive tumor microenvironments. Here we evaluated theability of DCs harbored in biocompatible scaffolds (referred to as biomatrixentrapped DCs; beDCs) in activating specific anti-tumor immune responsesagainst primary and post-surgery secondary tumors. Using a preclinical cervicalcancer and a melanoma model in mice, we show that single treatment of primaryand post-surgery secondary tumors using beDCs resulted in significant tumorgrowth retardation while multiple inoculations were required to achieve a significantanti-tumor effect when DCs were given in free form. Additionally, we foundthat, compared to the tumor specific E6/E7 peptide vaccine, total tumor lysateinduced higher expression of CD80 and CD40 on DCs that induced increased levelsof IFNγ production upon interaction with host lymphocytes. Remarkably, a strongimmunocyte infiltration into the host-implanted DC-scaffold was observed.Importantly, the host-implanted beDCs induced the anti-tumor immune responsesin the absence of any stromal cell support, and the biomatrix structure waseventually absorbed into the surrounding host tissue. Collectively, these dataindicate that the scaffold-based DC delivery may provide an efficient and safeway of delivering cell-based vaccines for treatment of primary and post-surgerysecondary tumors.http://www.ncbi.nlm.nih.gov/pubmed/27223431Oncotarget.2016 May 20. doi: 10.18632/oncotarget.9497. Zoledronic acidimpairs stromal reactivity by inhibiting M2-macrophages polarization andprostate cancer-associated fibroblasts.Zoledronic acid(ZA) is a biphosphonate used for osteoporosis treatment and also proved to beeffective to reduce the pain induced by bone metastases when used as adjuvanttherapy in solid cancers. However, it has been recently proposed that ZA couldhave direct anti-tumour effects, although the molecular mechanism is unknown.We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa),by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly,we demonstrate that ZA impairs PCa-induced M2-macrophages polarization,reducing their pro-invasive effect on tumour cells and their pro-angiogenicfeatures. Crucially, ZA administration reverts cancer associated fibroblasts(CAFs) activation by targeting the mevalonate pathway and RhoAgeranyl-geranylation, thereby impairing smooth muscle actin-α fibersorganization, a prerequisite of fibroblast activation. Moreover, ZA preventsthe M2 macrophages-mediated activation of normal fibroblast, highlighting thebroad efficacy of this drug on tumour microenvironment. These results areconfirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromalnormalization impairs cancer-stromal cells crosstalk, resulting in asignificant reduction of primary tumour growth and metastases. Overall thesefindings reinforce the efficacy of ZA as a potential therapeutic approach toreduce cancer aggressiveness, by abrogating the supportive role of tumourmicroenvironment.http://www.ncbi.nlm.nih.gov/pubmed/27224746Nanoscale.2016 Jun 2;8(22):11748-59. doi: 10.1039/c6nr02113a.The bright sideof plasmonic gold nanoparticles; activation of Nrf2, the cellular protectivepathway.GoldsteinA1, SorokaY2, Frušić-ZlotkinM2, LewisA3, KohenR2.Plasmonic goldnanoparticles (AuNPs) are widely investigated for cancer therapy, due to theirability to strongly absorb light and convert it to heat and thus selectivelydestroy tumor cells. In this study we shed light on a new aspect of AuNPs andtheir plasmonic excitation, wherein they can provide anti-oxidant andanti-inflammatory protection by stimulating the cellular protective Nrf2pathway. Our study was carried out on cells of the immune system, macrophages,and on skin cells, keratinocytes. A different response to AuNPs was noted inthe two types of cells, explained by their distinct uptake profiles. Inkeratinocytes, the exposure to AuNPs, even at low concentrations, wassufficient to activate the Nrf2 pathway, without any irradiation, due to thepresence of free AuNPs inside the cytosol. In contrast, in macrophages, theplasmonic excitation of the AuNPs by a low, non-lethal irradiation dose wasrequired for their release from the constraining vesicles. The mechanism bywhich AuNPs activate the Nrf2 pathway was studied. Direct and indirect activationwere suggested, based on the inherent ability of the AuNPs to react with thiolgroups and to generate reactive oxygen species, in particular, under plasmonicexcitation. The ability of AuNPs to directly activate the Nrf2 pathway rendersthem good candidates for treatment of disorders in which the up-regulation ofNrf2 is beneficial, specifically for topical treatment of inflammatory skindiseases. （细胞需要面对包含活性氧族和亲电子剂等多种微环境损害,它们通过多种机制应对有毒或致癌物质的损伤。其中最重要的细胞防御机制是通过转录因子Nrf2(nuclearfactor erythroid 2 p45 related factor 2)调节的。大量的研究均证实,Nrf2能够抵御广谱的毒性物质和致病原对细胞的损伤。Nrf2介导的细胞保护反应无细胞特异性和器官特异性,Nrf2可保护肺脏、肝脏、消化道、神经系统和心血管系统等多种器官或组织。因此,Nrf2在多器官保护中具有巨大的治疗潜力。）http://www.ncbi.nlm.nih.gov/pubmed/27225641Cancer Immunol Immunother.2016 Jul;65(7):857-67. doi: 10.1007/s00262-016-1849-y. Epub 2016 May 25.Myeloid-derivedsuppressor cells as intruders and targets: clinical implications in cancertherapy.Chronicinflammation, typical of various diseases including cancer, is a "silentbomb within the body," leading to complications that are only evident inmost cases upon their appearance, when disease is already deteriorated. Chronicinflammation is associated with accumulation of myeloid-derived suppressorcells (MDSCs), which lead to immunosuppression. MDSCs have numerous harmfuleffects as they support tumor initiation, tumor growth and spreading, which in turn,perpetuate the inflammatory and suppressive conditions, thus preventinganticancer responses. As the concept of the immune system combating many typesof tumors was revived in recent years, immunotherapy has dramatically changedthe view of cancer treatment, and numerous novel therapies have been developedand approved by the FDA. However, cumulative clinical data point at verylimited success rates. It is most likely that the developing chronicinflammation and MDSC-induced immunosuppression interfere with responses tosuch treatments and hence are major obstacles in achieving higher responserates to immune-based therapies. Moreover, chemotherapies were shown to haveadverse immunoregulatory effects, enhancing or decreasing MDSC levels andactivity, thus affecting treatment success. Therefore, therapeuticmanipulations of chronic inflammation and MDSCs during cancer development arelikely to enhance efficacy of immune- and chemo-based treatments, switchingchronic pro-cancer inflammatory environments to an anticancerous milieu. Basedon the functional relevance of immune networking in tumors, it is critical tomerge monitoring immune system biomarkers into the traditional patient'scategorization and treatment regimens. This will provide new tools for clinicalpractice, allowing appropriate management of cancer patients toward abetter-personalized medicine. http://www.ncbi.nlm.nih.gov/pubmed/27226545J Biol Chem. 2016 Jul1;291(27):14311-23. doi: 10.1074/jbc.M115.710350. Epub 2016 May 12.Characterizationof the Regulation of CD46 RNA Alternative Splicing.Here we present adetailed analysis of the alternative splicing regulation of human CD46, whichgenerates different isoforms with distinct functions. CD46 is a ubiquitousmembrane protein that protects host cells from complement and plays other rolesin immunity, autophagy, and cell adhesion. CD46 deficiency causes an autoimmunedisorder, and this protein is also involved in pathogen infection and cancer.Before this study, the mechanisms of CD46 alternative splicing remainedunexplored even though dysregulation of this process has been associated withautoimmune diseases. We proved that the 5' splice sites of CD46 cassette exons7 and 8 encoding extracellular domains are defined by noncanonical mechanismsof base pairing to U1 small nuclear RNA. Next we characterized the regulationof CD46 cassette exon 13, whose inclusion or skipping generates differentcytoplasmic tails with distinct functions. Using splicing minigenes, weidentified multiple exonic and intronic splicing enhancers and silencers thatregulate exon 13 inclusion via trans-acting splicing factors like PTBP1 andTIAL1. Interestingly, a common splicing activator such as SRSF1 appears torepress CD46 exon 13 inclusion. We also report that expression of CD46 mRNAisoforms is further regulated by non-sense-mediated mRNA decay andtranscription speed. Finally, we successfully manipulated CD46 exon 13inclusion using antisense oligonucleotides, opening up opportunities forfunctional studies of the isoforms as well as for therapeutics for autoimmunediseases. This study provides insight into CD46 alternative splicing regulationwith implications for its function in the immune system and for geneticdisease. Onco Targets Ther. 2016 May 4;9:2627-37.doi: 10.2147/OTT.S63049. eCollection 2016.Oncolyticviruses as immunotherapy: progress and remaining challenges.Oncolytic viruses(OVs) comprise an emerging cancer therapeutic modality whose activity involvesboth direct tumor cell lysis and the induction of immunogenic cell death (ICD).Cellular proteins released from the OV-lysed tumor cells, known asdamage-associated molecular patterns and tumor-associated antigens, activatedendritic cells and elicit adaptive antitumor immunity. Interaction with theinnate immune system and the development of long-lasting immune memory alsocontribute to OV-induced cell death. The degree to which the ICD componentcontributes to the clinical efficacy of OV therapy is still unclear. Modulationof a range of immune interactions may be beneficial or detrimental in natureand the interactions depend on the specific tumor, the site and extent of thedisease, the immunosuppressive tumor microenvironment, the OV platform, thedose, time, and delivery conditions, as well as individual patient responses.To enhance the contribution of ICD, OVs have been engineered to expressimmunostimulatory genes and strategies have been developed to combine OVtherapy with chemo- and immune-based therapeutic regimens. However, theseapproaches carry the risk that they may also be tolerogenic depending on theirlevels and the presence of other cytokines, their direct antiviral effects, andthe timing and conditions of their expression. The contribution of autophagy toadaptive immunity, the ability of the OVs to kill cancer stem cells, and thepatient's baseline immune status are additional considerations. This reviewfocuses on the complex and as yet poorly understood balancing act that dictatesthe outcome of OV therapy. We summarize current understanding of the OVs'function in eliciting antitumor immunity and its relationship to therapeuticefficacy. Also discussed are the criteria involved in restraining antiviralimmune responses and minimizing pathology while promoting antitumor immunity tooverride immune tolerance. TransfusMed Hemother. 2016 Mar;43(2):120-32. doi: 10.1159/000444941. Epub 2016 Mar8.★Until Death Do UsPart永不分离: Necrosis and Oxidation Promote the TumorMicroenvironment.Tumor proliferationis concomitant with autophagy, limited apoptosis, and resultant necrosis.Necrosis is associated with the release of damage-associated molecular patternmolecules (DAMPs), which act as 'danger signals', recruiting inflammatorycells, inducing immune responses, and promoting wound healing. Most of thecurrent treatment strategies for cancer (chemotherapy, radiation therapy,hormonal therapy) promote DAMP release following therapy-induced tumor death bynecroptosis and necrosis. Myeloid cells (monocytes, dendritic cells (DCs), andgranulocytes), as well as mesenchymal stromal cells (MSCs) belong to the earlyimmigrants in response to unscheduled cell death, initiating and modulating thesubsequent inflammatory response. Responding to DAMPs, MSCs, and DCs promote animmunosuppressive milieu, while eosinophils induce oxidative conditionslimiting the biologic activity of DAMPs over time and distance. Regulatory Tcells are strongly affected by pattern recognition receptor signaling in thetumor microenvironment and limit immune reactivity coordinately withmyeloid-derived suppressor cells. Means to 'aerobically' oxidize DAMPs providea novel strategy for limiting tumor progression. The present article summarizesour current understanding of the impact of necrosis on the tumormicroenvironment and the influence of oxidative conditions found within thissetting. CancerSci. 2016 May 26. doi: 10.1111/cas.12976. Dynamic changesin immune cell profile in head and neck squamous cell carcinoma:Immunomodulatory effects of chemotherapy.Tumor cells haveevolved sophisticated means of escape from the host immune system. To date,several important immunological phenomena have been revealed in peripheralblood as well as within tumors. In the present study, we first investigated theproportion and activation status of peripheral immune regulatory cells and CD8+T-cell subsets in patients with head and neck squamous cell carcinoma (HNSCC)using a multicolor flow cytometer, and then evaluated how therapy withdocetaxel, cisplatin, and 5-fluorouracil modulated the immune cell profile inperipheral blood. The proportion of naïve T cells was lower and that ofeffector memory T cells (TEM ) was higher in HNSCC patients than inhealthy donors. Moreover, the proportions of activated TEM cells andeffector T cells (TEFF ) were dramatically increased in patientswith advanced stage disease. The proportion of regulatory T cells and CD14+HLA-DR- myeloid-derived suppressor cells was elevated in HNSCCpatients. Of note, after therapy, in addition to the transient reduction inimmune regulatory cells, decreases in central memory T cells and increases in TEFFcells were observed among CD8+ T-cell subsets, suggestingdifferentiation from central memory T cells into TEFF cells. Ourresults suggested that, despite the immunosuppressive status in HNSCC patients,tumor-specific immune responses mediated by CD8+ T cells might beinduced and maintained. Moreover, chemotherapy can trigger not only a transientreduction in immune regulatory cells but also further activation of CD8+T cells. Oncotarget.2016 May 24. doi: 10.18632/oncotarget.9580. Using lymphnode swelling as a potential biomarker for successful vaccination.There is currentlya lack of biomarkers to help properly assess novel immunotherapies at both thepreclinical and clinical stages of development. Recent work done by our groupindicated significant volume changes in the vaccine draining right lymph node(RLN) volumes of mice that had been vaccinated with DepoVaxTM, a lipid-basedvaccine platform that was developed to enhance the potency of peptide-basedvaccines. These changes in lymph node (LN) volume were unique to vaccinatedmice.To better assess the potential of volumetric LN markers for multiplevaccination platforms, we evaluated 100 tumor bearing mice and assessed theirresponse to vaccination with either a DepoVax based vaccine (DPX) or awater-in-oil emulsion (w/o), and compared them to untreated controls. MRI wasused to longitudinally monitor LN and tumor volumes weekly over 4 weeks. Wethen evaluated changes in LN volumes occurring in response to therapy as apotential predictive biomarker for treatment success.We found that for bothvaccine types, DPX and w/o, the %RLN volumetric increase over baseline and theratio of RLN/LLN were strong predictors of successful tumor suppression (LLN isleft inguinal LN). The area under the curve (AUC) was greatest, between0.75-0.85, two (%RLN) or three (RLN/LLN) weeks post-vaccination. For optimizedcritical thresholds we found these biomarkers consistently had sensitivity >90%and specificity >70% indicating strong prognostic potential. Vaccinationwith DepoVax had a more pronounced effect on draining lymph nodes than w/oemulsion vaccines, which correlated with a higher anti-tumor activity inDPX-treated mice. Methods Mol Biol.2016;1428:115-23. doi: 10.1007/978-1-4939-3625-0_7.EngineeringWT1-Encoding mRNA to Increase Translational Efficiency in Dendritic Cells.Dendritic cells(DCs) are the orchestrators of the immune system and are frequently used inclinical trials in order to boost the immune system in cancer patients. Amongseveral available techniques for DC modification, mRNA electroporation is an interestingtechnique due to the favorable characteristics of mRNA. Antigen expressionlevel and duration can be increased by multiple optimizations of anantigen-encoding mRNA template. Here, we describe different molecularmodifications to a WT1-encoding mRNA construct in order to increase antigenexpression and the subsequent introduction of mRNA into DCs. Methods Mol Biol.2016;1428:261-76. doi: 10.1007/978-1-4939-3625-0_17.Transfection ofTumor-Infiltrating T Cells with mRNA Encoding CXCR2.Adoptive T-celltherapy based on the infusion of patient's own immune cells after ex vivoculturing is among the most potent forms of personalized treatment among recentclinical developments for the treatment of cancer. However, despite high ratesof successful initial clinical responses, only about 20 % of patients withmetastatic melanoma treated with tumor-infiltrating lymphocytes (TILs) enter completeand long-term regression, with the majority either relapsing after initialpartial regression or not benefiting at all. Previous studies have shown apositive correlation between the number infused T cells migrating to the tumorand the clinical response, but also that only a small fraction of adoptivelytransferred T cells reach the tumor site. In this chapter, we describe aprotocol for transfection of TILs with mRNA encoding the chemokine receptorCXCR2 transiently redirecting and improving TILs migration towardtumor-secreted chemokines in vitro. Toxins(Basel). 2016 May 28;8(6). pii: E165. doi: 10.3390/toxins8060165.CD133,Selectively Targeting the Root of Cancer.Cancer stem cells(CSC) are capable of promoting tumor initiation and self-renewal, two importanthallmarks of carcinoma formation. This population comprises a small percentageof the tumor mass and is highly resistant to chemotherapy, causing the most difficultproblem in the field of cancer research, drug refractory relapse. Many CSCmarkers have been reported. One of the most promising and perhaps leastubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequentlyexpressed on CSC. There is evidence that directly targeting CD133 withbiological drugs might be the most effective way to eliminate CSC. We haveinvestigated two entirely unrelated, but highly effective approaches forselectively targeting CD133. The first involves using a special anti-CD133single chain variable fragment (scFv) to deliver a catalytic toxin. The secondutilizes this same scFv to deliver components of the immune system. In thisreview, we discuss the development and current status of these CD133 associatedbiological agents. Together, they show exceptional promise by specific andefficient CSC elimination. Adv Exp Med Biol.2016;909:69-138. doi: 10.1007/978-94-017-7555-7_2.BiologicalResponse Modifier in Cancer Immunotherapy.Biologicalresponse modifiers (BRMs) emerge as a lay of new compounds or approaches usedin improving cancer immunotherapy. Evidences highlight that cytokines,Toll-like receptor (TLR) signaling, and noncoding RNAs are of crucial roles inmodulating antitumor immune response and cancer-related chronic inflammation,and BRMs based on them have been explored. In particular, besides somecytokines like IFN-α and IL-2, several Toll-like receptor (TLR) agonists likeBCG, MPL, and imiquimod are also licensed to be used in patients with severalmalignancies nowadays, and the first artificial small noncoding RNA (microRNA)mimic, MXR34, has entered phase I clinical study against liver cancer, implyingtheir potential application in cancer therapy. According to amounts of originaldata, this chapter will review the regulatory roles of TLR signaling, somenoncoding RNAs, and several key cytokines in cancer and cancer-related immuneresponse, as well as the clinical cases in cancer therapy based on them. Adv Exp Med Biol.2016;909:241-83. doi: 10.1007/978-94-017-7555-7_5.OncolyticImmunotherapy for Treatment of Cancer.Immunotherapyentails the treatment of disease by modulation of the immune system. Asdetailed in the previous chapters, the different modes of achieving immunemodulation are many, including the use of small/large molecules, cellulartherapy, and radiation. Oncolytic viruses that can specifically attack,replicate within, and destroy tumors represent one of the most promisingclasses of agents for cancer immunotherapy (recently termed as oncolyticimmunotherapy). The notion of oncolytic immunotherapy is considered as the wayin which virus-induced tumor cell death (known as immunogenic cancer cell death(ICD)) allows the immune system to recognize tumor cells and providelong-lasting antitumor immunity. Both immune responses toward the virus and ICDtogether contribute toward successful antitumor efficacy. What is now becomingincreasingly clear is that monotherapies, through any of the modalitiesdetailed in this book, are neither sufficient in eradicating tumors nor inproviding long-lasting antitumor immune responses and that combinationtherapies may deliver enhanced efficacy. After the rise of the geneticengineering era, it has been possible to engineer viruses to harborcombination-like characteristics to enhance their potency in cancerimmunotherapy. This chapter provides a historical background on oncolyticvirotherapy and its future application in cancer immunotherapy, especially as acombination therapy with other treatment modalities. Exp Dermatol. 2016 Jun 1. doi:10.1111/exd.13095. Combining achimeric antigen receptor and a conventional T-cell receptor to generate Tcells expressing two additional receptors (TETARs) for a multi-hitimmunotherapy of melanoma.The adoptivetransfer of engineered T cells represents an important approach inimmunotherapy of melanoma. However, relapse of the tumor can occur due toimmune escape mechanisms developed by the tumor cells, e.g. antigen loss,down-regulation of the MHC presentation machinery, and defects in antigenprocessing. To counteract these mechanisms, we combined a T-cell receptor and achimeric antigen receptor, specific for different common melanoma antigens,gp100 (PMEL) and MCSP (HMW-MAA), to generate functional CD8+ T cellsexpressing two additional receptors (TETARs) by electroporation ofreceptor-encoding mRNA. These TETARs produced cytokines and were lytic uponrecognition of each of their cognate antigens, while no reciprocal inhibitionof the receptors occurred. When stimulated with target cells, which expressboth antigens, an enhanced effect was suggested. The confirmation that chimericantigen receptors and T-cell receptors can be functionally combined opens upnew avenues in cancer immunotherapy and the generation of TETARs helpsby-passing major mechanisms by which tumor cells escape immune recognition. Oncotarget.2016 May 27. doi: 10.18632/oncotarget.9598. A key role ofGARP in the immune suppressive tumor microenvironment.In melanomapatients, one of the main reasons for tumor immune escape and therapy failureis the immunosuppressive tumor microenvironment. Herein, suppressive immunecells and inhibitory factors secreted by the tumor itself play a centralrole.In the present study we show that the Treg activation marker GARP (glycoproteinA repetitions predominant), known to induce peripheral tolerance ina TGF-β dependent way, is also expressed on human primary melanoma.Interestingly, membrane bound GARP is shed from the surface of both, activatedTreg and melanoma cells, and, in its soluble form (sGARP), not only inducesperipheral Treg but also a tumor associated (M2) macrophage phenotype. Notably,proliferation of cytotoxic T cells and their effector function is inhibited inthe presence of sGARP. GARP expression on Treg and melanoma cells issignificantly decreased in the presence of agents such as IFN-α, thusexplaining at least in part a novel mechanism of action of this adjuvanttherapy.In conclusion, GARP in its soluble and membrane bound form contributesto peripheral tolerance in a multipronged way, potentiates theimmunosuppressive tumor microenvironment and thus acts as a negative regulatorin melanoma patients. Therefore, it may qualify as a promising target and a newcheckpoint for cancer immunotherapy. Oncotarget.2016 May 27. doi: 10.18632/oncotarget.9660. Immunogenicityof mammary tumor cells can be induced by shikonin via directbinding-interference with hnRNPA1.Immunogenic celldeath (ICD) of tumor cells occurs via various pathways that activate immunecell systems against cancer. Previous studies have demonstrated that shikonin(SK), a plant secondary metabolite, can confer strong pharmacologicalactivities that activate ICD and strong immunogenicity of tumor cells. However,the exact hierarchical regulatory mechanisms including the molecular targets ofSK-activated immunogenicity are still unknown. Here, the heterogeneous nuclearribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific proteintarget for SK. This binding plays a key role in SK-stimulated ICD activity andthe suppression of post-transcriptional mRNA processing, including nuclearexport activity of newly synthesized mRNAs in mammary carcinoma cells in vitro.Moreover, it also mechanistically mediates the anti-metastatic effect of atumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity ofSK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1as the intracellular molecular target provides compelling pharmacology-basedknowledge for the potential clinical use of SK-induced immunogenicity. Inaddition, SK may also serve as a potent suppressor that interferes with specificpost-transcriptional activities, a mechanism which may be useful forexploitation in cancer therapeutics. Oncotarget.2016 May 27. doi: 10.18632/oncotarget.9674. Expression andfunctional characterization of CD33 transcript variants in human acute myeloidleukemia.With thedemonstration of improved survival of some acute myeloid leukemia (AML)patients with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO),CD33 has been validated as a target for antigen-specific immunotherapy. Sinceprevious studies identified a CD33 splice variant missing exon 2 (CD33∆E2)and, consequently, the immune-dominant membrane-distal V-set domain, we investigatedthe expression and functional characteristics of CD33 transcript variants inAML. In primary AML specimens, we not only found full-length CD33 (CD33FL) andCD33∆E2 but also corresponding variants containing an alternate exon 7predicted to encode a CD33 protein lacking most of the intracellular domain(CD33E7a and, notpreviously described, CD33∆E2,E7a)in almost all cases. In acute leukemia cell sublines engineered to expressindividual CD33 splice variants, all splice variants had endocytic properties.CD33FL and CD33E7a mediatedsimilar degrees of GO cytotoxicity, whereas CD33∆E2 and CD33∆E2,E7a could not serve as target for GO.Co-expression of CD33∆E2 did not interfere with CD33FL endocytosis and didnot impact CD33FL-mediated GO cytotoxicity. Together, our findings document agreater-than-previously thought complexity of CD33 expression in human AML.They identify CD33 variants that lack exon 2 and are not recognized by currentCD33-directed therapeutics as potential target for future unconjugated orconjugated antibodies. AmSoc Clin Oncol Educ Book. 2016;35:e450-8. doi: 10.14694/EDBK_158712.Immunotherapy:Beyond Anti-PD-1 and Anti-PD-L1 Therapies.Advanced-stagenon-small cell lung cancer (NSCLC) and small cell lung cancer are cancers inwhich chemotherapy produces a survival benefit, although it is small. We nowknow that anti-PD-1/PD-L1 has substantial clinical activity in both of thesediseases, with an overall response rate (ORR) of 15%-20%. These responses arefrequently rapid and durable, increase median overall survival (OS) comparedwith chemotherapy, and produce long-term survivors. Despite these verysignificant results, many patients do not benefit from anti-PD-1/PD-L1. This isbecause of the potential for malignancies to co-opt myriad immunosuppressivemechanisms other than aberrant expression of PD-L1. Conceptually, these can bedivided into three categories. First, for some patients there is likely afailure to generate sufficient functional tumor antigen-specific T cells.Second, for others, tumor antigen-specific T cells may be generated but fail toenter into the tumor parenchyma. Finally, there are a large number ofimmunosuppressive mechanisms that have the potential to be operational withinthe tumor microenvironment: surface membrane immune checkpoint proteins PD-1,CTLA-4, LAG3, TIM3, BTLA, and adenosine A2AR; soluble factors and metabolicalterations interleukin (IL)-10, transforming growth factor (TGF)-β, adenosine,IDO, and arginase精氨酸酶; and inhibitory cells, cancer-associatedfibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells(MDSCs), and tumor-associated macrophages. In this article, we discuss threestrategies to generate more tumor-reactive T cells for patients: anti-CTLA-4,therapeutic tumor vaccination, and adoptive cellular therapy, with T cellsredirected to tumor antigens using T-cell receptor (TCR) or chimeric antigenreceptor (CAR) gene modification. We also review some of the various strategiesin development to thwart tumor microenvironment immunosuppressive mechanisms.Strategies to drive more T cells into tumors remain a significant challenge. Mol Cancer Ther. 2016 Jun 2. ERK1 as aTherapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas.Glioma regressionrequires the recruitment of potent antitumor immune cells into the tumormicroenvironment. Dendritic cells (DC) play a role in immune responses to thesetumors. The fact that DC vaccines do not effectively combat high-grade gliomas,however, suggests that DCs need to be genetically modified specifically topromote their migration to tumor relevant sites. Previously, we identifiedextracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicityand brain autoimmunity. In the current study, we made use of modern magneticresonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model ofhigh-grade glioma. We found that ERK1-deficient mice are more resistant to thedevelopment of gliomas, and tumor growth in these mice is accompanied by ahigher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase inmigration that is associated with sustained Cdc42 activation and increasedexpression of actin-associated cytoskeleton-organizing proteins. We alsodemonstrated that ERK1 deletion potentiates DC vaccination and provides asurvival advantage in high-grade gliomas. Considering the therapeuticsignificance of these results, we propose ERK1-deleted DC vaccines as anadditional means of eradicating resilient tumor cells and preventing tumorrecurrence. SciRep. 2016 Jun 3;6:27136. doi: 10.1038/srep27136.Cryo-thermaltherapy elicits potent anti-tumor immunity by inducing extracellularHsp70-dependent MDSC differentiation.Achieving controlof metastatic disease is a long-sought goal in cancer therapy. Treatments thatencourage a patient's own immune system are bringing new hopes in reaching sucha goal. In clinic, local hyperthermia and cryoablation have been explored toinduce anti-tumor immune responses against tumors. We have also developed anovel therapeutic modality of cryo-thermal treatment by alternating liquidnitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeuticeffect was achieved in treating metastatic cancer in animal model. In thisstudy, we investigated the mechanism of systemic immune response elicited bycryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found thatlocal cryo-thermal therapy resulted in a considerable reduction of distant lungmetastases, and improved long-term survival. Moreover, results of tumorre-challenge experiments indicated generation of a strong tumor-specific immunememory after the local treatment of primary tumors. Our further study indicatedthat cryo-thermal therapy caused an elevated extracellular release of Hsp70.Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs,contributing to the relief of MDSCs-mediated immunosuppression and ultimatelythe activation of strong anti-tumor immune response. Our findings reveal newinsight into the mechanism of robust therapeutic effects of cryo-thermaltherapy against metastatic cancers. J Leukoc Biol. 2016 Jun 2. pii: jlb.5A0116-053RR. mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D andTNF-α.γδ T cells play acritical role in early anti-tumor immunity and perform cytotoxicity via NKG2Dfor recognition and multiple cytotoxic factors for tumor killing. Recentstudies have demonstrated pivotal roles of mTOR-mediated metabolism in thematuration, differentiation, and effector function of diverse immune cells,including DCs, NK cells, CD4+ T cell subsets, and CD8+ Tcells, but the role of mTOR signaling in γδ T cells is barely known. Here, weshowed that suppressing mTOR signaling in in vitro-expanded Vγ4 γδ T cells viathe mechanistic inhibitor rapamycin enhanced their cytotoxicity againstmultiple tumor cell lines, and these cells performed better tumor-suppressingeffects upon adoptive therapy. Further investigation revealed that elevatedcytotoxicity was a result of up-regulation of NKG2D and TNF-α. Moreover,rapamycin treatment significantly decreased the expression of CISH andincreased pSTAT5. The inhibition of STAT5 pathways via siRNA interference or aspecific inhibitor eliminated the up-regulation of NKG2D and TNF-α inrapamycin-treated Vγ4 γδ T cells. These results uncovered an important role ofmTOR signaling in the cytotoxic effector function of γδ T cells and provided apotential strategy to improve γδ T cell-based cancer immunotherapy. J Leukoc Biol. 2016 Jun 2. pii:jlb.5RI0116-013RR. Combinatorialapproach to cancer immunotherapy: strength in numbers.Immune-checkpointblockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionizedmelanoma treatment by eliciting responses that can be remarkably durable and isnow advancing to other malignancies. However, not all patients respond toimmune-checkpoint inhibitors. Extensive preclinical evidence suggests thatcombining immune-checkpoint inhibitors with other anti-cancer treatments cangreatly improve the therapeutic benefit. The first clinical success of thecombinatorial approach to cancer immunotherapy was demonstrated using adual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted inaccelerated FDA approval of this therapeutic regimen. In this review, wediscuss the combinations of current and emerging immunotherapeutic agents inclinical and preclinical development and summarize the insights into potentialmechanisms of synergistic anti-tumor activity gained from animal studies. Thesepromising combinatorial partners for the immune-checkpoint blockade includetherapeutics targeting additional inhibitory receptors of T cells, such asTIM-3, LAG-3, TIGIT, and BTLA, and agonists of T cell costimulatory receptors4-1BB, OX40, and GITR, as well as agents that promote cancer cell recognitionby the immune system, such as tumor vaccines, IDO inhibitors, and agonists ofthe CD40 receptor of APCs. We also review the therapeutic potential of regimenscombining the immune-checkpoint blockade with therapeutic interventions thathave been shown to enhance immunogenicity of cancer cells, including oncolyticviruses, RT, epigenetic therapy, and senescence-inducing therapy. J Biomed Nanotechnol. 2016Apr;12(4):700-9.Folate-ModifiedChitosan Nanoparticles Coated Interferon-Inducible Protein-10 Gene EnhanceCytotoxic T Lymphocytes' Responses to Hepatocellular Carcinoma.Adoptive therapyusing tumor antigen-specific cytotoxic T lymphocytes (CTLs) is a promisingapproach for treatment of human cancers. Due to immune suppression in cancerpatients, it is difficult for tumor antigen-specific CTLs to arrive at tumortissues. Interferon-inducible protein-10 (IP-10) is a powerful chemokine thateffectively attracts CTLs to tumor tissues and improves their anti-tumoractivity. Increase over expression of IP-10 in tumor tissues can efficiently promote efficacy of adoptivetherapy. Folate-modified chitosan nanoparticles coating the human IP-10 gene(FA-CS-hIP-10) were therefore developed in this study. The FA-CS-hIP-10nanoparticles were specifically bound to folate receptors on hepatoma cells andpromoted the expression of IP-10, to improve the activity of pMAGE-A1(278-286)specific CTLs. Combination of the FA-CS-hIP-10 and pMAGE-A1(278-286) specificCD8+ CTLs efficiently increased secretion of IFN-γ, inhibited tumor growth andextended survival of nude mice with subcutaneously transplanted humanhepatocellular carcinoma. Our results demonstrated that the mechanism behindthis novel therapeutic approach involved inhibition of angiogenesis andproliferation, and also promoted apoptosis of tumor cells. Our study provides apotentially novel approach for treatment of human hepatocellular carcinoma byimproving the activity of tumor antigen-specific CTLs. CancerDiscov. 2016 Jun 13. pii: CD-15-1412. Autocrine Complement Inhibits IL10-Dependent T-Cell Mediated AntitumorImmunity to Promote Tumor Progression.In contrast to itsinhibitory effects on many cells, IL-10 activates CD8+ tumor infiltratinglymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs donot routinely express IL-10 as autocrine complement C3 inhibits IL-10production through complement receptors C3aR and C5aR. CD8+ TILs fromC3-deficient mice, however, express IL-10 and exhibit enhanced effectorfunction. C3-deficient mice are resistant to tumor development in a T cell- andIL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase thekilling of primary tumors in vitro compared to IL-2 treated TILs.Complement-mediated inhibition of antitumor immunity is independent of thePD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complementreceptors C3aR and C5aR expressed on CD8+ TILs represent a novel class ofimmune checkpoints that could be targeted for tumor immunotherapy. Moreover,incorporation of IL-10 in theexpansion of TILs and in gene-engineered T cells for adoptive cell therapyenhances their antitumor efficacy. CancerMed. 2016 Jun 12. doi: 10.1002/cam4.754. Higherpreoperative serum levels of PD-L1 and B7-H4 are associated with invasive andmetastatic potential and predictable for poor response to VEGF-targeted therapyand unfavorable prognosis of renal cell carcinoma.Renal cell carcinoma(RCC) is an immunogenic and proangiogenic cancer. Although antivascularendothelial growth factor (VEGF) therapies achieve impressive responses in somepatients, many tumors eventually develop resistance to such therapy. The B7family molecules such as CTLA-4, PD-1, and PD-L1 are pivotal players in immunecheckpoints that positively or negatively regulate various immune responses.Recently, immunotherapy based on blocking immune checkpoints with anti-CTLA4,anti-PD-1, or anti-PD-L1 antibodies has been proposed as a potential newapproach to the treatment of metastatic RCC. Higher expression of PD-L1 andB7-H4 in the tumors isassociated with a poor prognosis in RCCs, however, the clinical impact of serumlevels of B7 family molecules has not been elucidated in patients withmetastatic RCCs receiving VEGF-targeted agents. We assessed the preoperativeserum levels of B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3,B7-H4, and CTLA-4, and CD28 inRCC patients, and determined their relations with various clinicopathologicalcharacteristics. Elevated preoperative serum levels of PD-L1 and B7-H4 werecorrelated with less differentiated tumors, higher invasive and metastaticpotential, a worse response to anti-VEGF therapy, and shorter overall survival.These findings suggested that investigating preoperative serum levels of PD-L1and B7-H4 might not only be useful to assess the biological aggressiveness ofRCCs, but also to predict the efficacy of anti-VEGF therapy and the eventualprognosis, indicating the future design of clinical trials of therapiestargeting immune checkpoint in advanced RCCs. Cancer Immunol Res. 2016 Jun 10. LenalidomideInduces Interleukin-21 Production by T Cells and Enhances IL21-MediatedCytotoxicity in Chronic Lymphocytic Leukemia B Cells.来那度胺，TNFa抑制剂Theimmunomodulatory drug lenalidomide has demonstrated efficacy in patients withchronic lymphocytic leukemia (CLL), despite a lack of direct cytotoxic effectsin vitro The mechanism of lenalidomide efficacy in vivo is thought to occur viaa combination of enhanced immune activity and an alteration of tumorcell-microenvironment interactions. We demonstrate in whole blood from patientswith CLL that lenalidomide significantly depletes malignant B cells.Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in Tcells from patients with CLL. In addition, lenalidomide enhanced upregulationof functional IL21 receptor (IL21R) on the cell surface and increased receptormRNA in vitro The in vitro combination of IL21 and lenalidomide enhancedIL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. Weshow association of cell death with upregulation of Bid by IL21, enhancedupregulation of Bid by the combination therapy, and diminished Lck anddownstream BCR signaling activation of Syk and PLCG2. Collectively, wedemonstrated an immune cell-tumor cell interaction throughlenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediatedcytotoxicity, which provides justification for this combination in clinicaltrials for patients with CLL Semin Cell Dev Biol.2016 Jun 7. pii: S1084-9521(16)30166-5. doi: 10.1016/j.semcdb.2016.06.004. Pathogenmimicry of host protein-protein interfaces modulates immunity.Signaling pathwaysshape and transmit the cell's reaction to its changing environment; however,pathogens can circumvent this response by manipulating host signaling. Tosubvert host defense, they beat it at its own game: they hijack host pathwaysby mimicking the binding surfaces of host-encoded proteins. For this, it is notnecessary to achieve global protein homology; imitating merely the interactionsurface is sufficient. Different protein folds often interact via similarprotein-protein interface architectures. This similarity in binding surfacespermits the pathogenic protein to compete with a host target protein. Thus,rather than binding a host-encoded partner, the host protein hub binds thepathogenic surrogate. The outcome can be dire: rewiring or repurposing the hostpathways, shifting the cell signaling landscape and consequently the immuneresponse. They can also cause persistent infections as well as cancer bymodulating key signaling pathways, such as those involving Ras. Mapping therewired host-pathogen 'superorganism' interaction network - along with itsstructural details - is critical for in-depth understanding of pathogenicmechanisms and developing efficient therapeutics. Here, we overview the role ofmolecular mimicry in pathogen host evasion as well as types of molecularmimicry mechanisms that emerged during evolution. PLoSOne. 2016 Jun 10;11(6):e0156643. doi: 10.1371/journal.pone.0156643.eCollection 2016.Epirubicin,Identified Using a Novel Luciferase Reporter Assay for Foxp3 Inhibitors,Inhibits Regulatory T Cell Activity. 盐酸表柔比星Forkhead boxprotein p3 (Foxp3) is crucial to the development and suppressor function ofregulatory T cells (Tregs) that have a significant role in tumor-associatedimmune suppression. Development of small molecule inhibitors of Foxp3 functionis therefore considered a promising strategy to enhance anti-tumor immunity. Inthis study, we developed a novel cell-based assay system in which the NF-κBluciferase reporter signal is suppressed by the co-expressed Foxp3 protein.Using this system, we screened our chemical library consisting of approximately2,100 compounds and discovered that a cancer chemotherapeutic drug epirubicinrestored the Foxp3-inhibited NF-κB activity in a concentration-dependent mannerwithout influencing cell viability. Using immunoprecipitation assay in aTreg-like cell line Karpas-299, we found that epirubicin inhibited theinteraction between Foxp3 and p65. In addition, epirubicin inhibited thesuppressor function of murine Tregs and thereby improved effector T cellstimulation in vitro. Administration of low dose epirubicin into tumor-bearingmice modulated the function of immune cells at the tumor site and promotedtheir IFN-γ production without direct cytotoxicity. In summary, we identifiedthe novel action of epirubicin as a Foxp3 inhibitor using a newly establishedluciferase-based cellular screen. Our work also demonstrated our screen systemis useful in accelerating discovery of Foxp3 inhibitors. Oncotarget.2016 Jun 7. doi: 10.18632/oncotarget.9871. Profiling thedynamic expression of checkpoint molecules on cytokine-induced killer cellsfrom non-small-cell lung cancer patients.Immune checkpointsassociate with dysfunctional T cells, which have a reduced ability to clearpathogens or cancer cells. T-cell checkpoint blockade may improve patientsurvival. However, checkpoint molecules on cytokine-induced killer (CIK) cell,a non-specific adoptive immunotherapy, remain unknown. In present study, wedetected the dynamic expression of eight major checkpoint molecules (CTLA-4,PD-1, PD-L1, TIM- 3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLCpatients. The majority of these molecules, except BTLA, were sharply elevatedduring the early stage of CIK cell culture. Thereafter, PD-1 and TIGITexpressions decreased gradually towards the initial level (day 0). Moreover,CTLA-4 faded away during the later stage of CIK culture. LAG-3 expressiondecreased but was still significantly higher than the initial level. Of note,PD-L1 remained stably upregulated during CIK culture compared with PD-1,indicating that PD-L1 might act as an inhibitory molecule on CIK cells insteadof PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneouslyduring long-term CIK culture and showed a significant and mutually positivecorrelation. BTLA displayed a distinct pattern, and its expression graduallydecreased throughout the CIK culture. These observations suggested that CIK cellsmight be partly exhausted before clinical transfusion, characterized by thehigh expression of PD-L1, LAG-3, TIM- 3, and CEACAM-1 and the low expression ofTIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results implythat implementing combined treatment on CIK cells before transfusion viaantibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve theefficiency of CIK therapy for NSCLC patients. Nature.2016 Jun 1;534(7607):396-401. doi: 10.1038/nature18300.Systemic RNAdelivery to dendritic cells exploits antiviral defence for cancerimmunotherapy.Lymphoid organs,in which antigen presenting cells (APCs) are in close proximity to T cells, arethe ideal microenvironment for efficient priming and amplification of T-cellresponses. However, the systemic delivery of vaccine antigens into dendriticcells (DCs) is hampered by various technical challenges. Here we show that DCscan be targeted precisely and effectively in vivo using intravenouslyadministered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers byoptimally adjusting net charge, without the need for functionalization ofparticles with molecular ligands. The LPX protects RNA from extracellularribonucleases and mediates its efficient uptake and expression of the encodedantigen by DC populations and macrophages in various lymphoid compartments.RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs andmacrophages. Consequently, DC maturation in situ and inflammatory immunemechanisms reminiscent of those in the early systemic phase of viral infectionare activated. We show that RNA-LPX encoding viral or mutant neo-antigens orendogenous self-antigens induce strong effector and memory T-cell responses,and mediate potent IFNα-dependent rejection of progressive tumours. A phase Idose-escalation trial testing RNA-LPX that encode shared tumour antigens isongoing. In the first three melanoma patients treated at a low-dose level, IFNαand strong antigen-specific T-cell responses were induced, supporting theidentified mode of action and potency. As any polypeptide-based antigen can beencoded as RNA, RNA-LPX represent a universally applicable vaccine class forsystemic DC targeting and synchronized induction of both highly potent adaptiveas well as type-I-IFN-mediated innate immune mechanisms for cancerimmunotherapy. Int J Oncol. 2016Aug;49(2):793-802. doi: 10.3892/ijo.2016.3567. Epub 2016 Jun 7.Naltrexone atlow doses upregulates a unique gene expression not seen with normal doses:Implications for its use in cancer therapy.纳曲酮It has beenreported that lower doses of the opioid antagonist naltrexone are able toreduce tumour growth by interfering with cell signalling as well as bymodifying the immune system. We have evaluated the gene expression profile of acancer cell line after treatment with low-dose naltrexone (LDN), and assessedthe effect that adapting treatment schedules with LDN may have on enhancingefficacy. LDN had a selective impact on genes involved with cell cycleregulation and immune modulation. Similarly, the pro-apoptotic genes BAD andBIK1 were increased only after LDN. Continuous treatment with LDN had littleeffect on growth in different cell lines; however, altering the treatmentschedule to include a phase of culture in the absence of drug following aninitial round of LDN treatment, resulted in enhanced cell killing. Furthermore,cells pre-treated with LDN were more sensitive to the cytotoxic effects of anumber of common chemotherapy agents. For example, priming HCT116 with LDNbefore treatment with oxaliplatin significantly increased cell killing to49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly,priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Ourdata support further the idea that LDN possesses anticancer activity, which canbe improved by modifying the treatment schedule. Int J Oncol. 2016Aug;49(2):471-8. doi: 10.3892/ijo.2016.3540. Epub 2016 May 27.Clonalexpansion of antitumor T cells in breast cancer correlates with response toneoadjuvant chemotherapy.The immunemicroenvironment of tumor plays a critical role in therapeutic responses tochemotherapy. Cancer tissues are composed of a complex network betweenantitumor and pro-tumor immune cells and molecules; therefore a comprehensiveanalysis of the tumor immune condition is imperative for better understandingof the roles of the immune microenvironment in anticancer treatment response. Inthis study, we performed T cell receptor (TCR) repertoire analysis of tumorinfiltrating T cells (TILs) in cancer tissues of pre- and post-neoadjuvantchemotherapy (NAC) from 19 breast cancer patients; five cases showed CR(complete response), ten showed PR (partial response), and four showed SD/PD(stable disease/progressive disease) to the treatment. From the TCR sequencingresults, we calculated the diversity index of the TCRβ chain and found thatclonal expansion of TILs could be detected in patients who showed CR or PR toNAC. Noteworthy, the diversity of TCR was further reduced in the post-NACtumors of CR patients. Our quantitative RT-PCR also showed that expressionratio of CD8/Foxp3 was significantly elevated in the post-NAC tumors of CRcases (p=0.0032), indicating that antitumor T cells were activated and enrichedin these tumors. Collectively, our findings suggest that the clonal expansionof antitumor T cells may be a critical factor associated with response tochemotherapy and that their TCR sequences might be applicable for thedevelopment of TCR-engineered T cells treatment for individual breast cancerpatients when their tumors relapse. Int J Mol Sci. 2016Jun 6;17(6). pii: E891. doi: 10.3390/ijms17060891.IntravenousAdministration Is an Effective and Safe Route for Cancer Gene Therapy Using theBifidobacterium-Mediated Recombinant HSV-1 Thymidine Kinase and Ganciclovir.更昔洛韦The herpes simplexvirus thymidine kinase/ganciclovir (HSV TK/GCV) system is one of the beststudied cancer suicide gene therapy systems. Our previous study showed thatcaspase 3 expression was upregulated and bladder tumor growth was significantlyreduced in rats treated with a combination of Bifidobacterium (BF) and HSVTK/GCV (BF-rTK/GCV). However, it was raised whether the BF-mediated recombinantthymidine kinase combined with ganciclovir (BF-rTK/GCV) was safe to administervia venous for cancer gene therapy. To answer this question, the antitumoreffects of BF-rTK/GCV were mainly evaluated in a xenograft nude mouse modelbearing MKN-45 gastric tumor cells. The immune response, including analysis ofcytokine profiles, was analyzed to evaluate the safety of intramuscular andintravenous injection of BF-rTK in BALB/c mice. The results suggested thatgastric tumor growth was significantly inhibited in vivo by BF-rTK/GCV.However, the BF-rTK/GCV had no effect on mouse body weight, indicating that thetreatment was safe for the host. The results of cytokine profile analysisindicated that intravenous injection of a low dose of BF-rTK resulted in aweaker cytokine response than that obtained with intramuscular injection.Furthermore, immunohistochemical analysis showed that intravenousadministration did not affect the expression of immune-associated TLR2 andTLR4. Finally, the BF-rTK/GCV inhibited vascular endothelial growth factor(VEGF) expression in mouse model, which is helpful for inhibiting of tumor angiogenesis.That meant intravenous administration of BF-rTK/GCV was an effective and safeway for cancer gene therapy. Rev Med Virol. 2016 Jun 8. doi: 10.1002/rmv.1892.The Wntpathway: a key network in cell signalling dysregulated by viruses.Viruses areobligate parasites dependent on host cells for survival. Viral infection of acell activates a panel of pattern recognition receptors that mediate antiviralhost responses to inhibit viral replication and dissemination. Viruses haveevolved mechanisms to evade and subvert this antiviral host response, includingencoding proteins that hijack, mimic and/or manipulate cellular processes suchas the cell cycle, DNA damage repair, cellular metabolism and the host immuneresponse. Currently, there is an increasing interest whether viral modulationof these cellular processes, including the cell cycle, contributes to cancerdevelopment. One cellular pathway related to cell cycle signalling is the Wntpathway. This review focuses on the modulation of this pathway by humanviruses, known to cause (or associated with) cancer development. The mainmechanisms where viruses interact with the Wnt pathway appear to be through (i)epigenetic modification of Wnt genes; (ii) cellular or viral miRNAs targetingWnt genes; (iii) altering specific Wnt pathway members, often leading to (iv)nuclear translocation of β-catenin and activation of Wnt signalling. Given thatdiverse viruses affect this signalling pathway, modulating Wnt signalling couldbe a generalised critical process for the initiation or maintenance of viralpathogenesis, with resultant dysregulation contributing to virus-inducedcancers. Further study of this virus-host interaction may identify options fortargeted therapy against Wnt signalling molecules as a means to reducevirus-induced pathogenesis and the downstream consequences of infection. JClin Oncol. 2016 Jun 6. pii: JCO655142. T-Cell TherapyUsing Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined WithCytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term CellPersistence and Durable Tumor Regression.PURPOSE: Peripheralblood-derived antigen-specific cytotoxic T cells (CTLs) provide a readilyavailable source of effector cells that can be administered with minimaltoxicity in an outpatient setting. In metastatic melanoma, this approachresults in measurable albeit modest clinical responses in patients resistant toconventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyteantigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity ofadoptively transferred CTLs.PATIENTS ANDMETHODS: AutologousMART1-specific CTLs were generated by priming with peptide-pulsed dendriticcells in the presence of interleukin-21 and enriched by peptide-majorhistocompatibility complex multimer-guided cell sorting. This expeditiouslyyielded polyclonal CTL lines uniformly expressing markers associated with anenhanced survival potential. In this first-in-human strategy, 10 patients withstage IV melanoma received the MART1-specific CTLs followed by a standardcourse of anti-CTLA-4 (ipilimumab).RESULTS: The toxicityprofile of the combined treatment was comparable to that of ipilimumabmonotherapy. Evaluation of best responses at 12 weeks yielded two continuouscomplete remissions, one partial response (PR) using RECIST criteria (two PRsusing immune-related response criteria), and three instances of stable disease.Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cellsfor as long as the patients were monitored (up to 40 weeks). In patients whoexperienced complete remissions, PRs, or stable disease, the persisting CTLsacquired phenotypic and functional characteristics of long-lived memory cells.Moreover, these patients also developed responses to nontargeted tumor antigens(epitope spreading).CONCLUSION: We demonstratethat combining antigen-specific CTLs with CTLA-4 blockade is safe and producesdurable clinical responses, likely reflecting both enhanced activity oftransferred cells and improved recruitment of new responses, highlighting thepromise of this strategy. SciRep. 2016 Jun 6;6:27232. doi: 10.1038/srep27232.Mycobacteriaemulsified in olive oil-in-water trigger a robust immune response in bladdercancer treatment.The hydrophobiccomposition of mycobacterial cell walls leads to the formation of clumps whenattempting to resuspend mycobacteria in aqueous solutions. Such aggregation mayinterfere in the mycobacteria-host cells interaction and, consequently,influence their antitumor effect. To improve the immunotherapeutic activity ofMycobacterium brumae, we designed different emulsions and demonstrated theirefficacy. The best formulation was initially selected based on homogeneity andstability. Both olive oil (OO)- and mineral oil-in-water emulsions betterpreserved the mycobacteria viability and provided higher disaggregation ratescompared to the others. But, among both emulsions, the OO emulsion increasedthe mycobacteria capacity to induce cytokines' production in bladder tumor cellcultures. The OO-mycobacteria emulsion properties: less hydrophobic, lower pH,more neutralized zeta potential, and increased affinity to fibronectin thannon-emulsified mycobacteria, indicated favorable conditions for reaching thebladder epithelium in vivo. Finally, intravesical OO-M. brumae-treated miceshowed a significantly higher systemic immune response, together with a trendtoward increased tumor-bearing mouse survival rates compared to the rest of thetreated mice. The physicochemical characteristics and the induction of a robustimmune response in vitro and in vivo highlight the potential of the OO emulsionas a good delivery vehicle for the mycobacterial treatment of bladder cancer. TrendsMol Med. 2016 Jul;22(7):565-77. doi:10.1016/j.molmed.2016.05.007. Epub 2016 Jun 1.Exercise-DependentRegulation of NK Cells in Cancer Protection.Natural killer(NK) cells are the most responsive immune cells to exercise, displaying anacute mobilization to the circulation during physical exertion. Recently,exercise-dependent mobilization of NK cells was found to play a central role inexercise-mediated protection against cancer. Here, we review the link betweenexercise and NK cell function, focusing on circulating exercise factors andadditional effects, including vascularization, hypoxia, and body temperature inmediating the effects on NK cell functionality. Exercise-dependent mobilizationand activation of NK cells provides a mechanistic explanation for theprotective effect of exercise on cancer, and we propose that exerciserepresents a potential strategy as adjuvant therapy in cancer, by improving NKcell recruitment and infiltration in solid tumors. Cancer Immunol Res. 2016 Jun 4. Interferon-γProduction by Peripheral Lymphocytes Predicts Survival of Tumor-Bearing MiceReceiving Dual PD-1/CTLA-4 Blockade.Immune checkpointinhibitors are transforming the way cancer is treated. However, these therapiesdo not benefit all patients and frequently cause significant immune-relatedadverse events. Biomarkers that identify patients with a favorable earlyresponse to therapy are essential for guiding treatment decisions and improvingpatient outcomes. In this report of our study, we present evidence that shortlyafter administration of dual PD-1/CTLA-4 blockade, the proinflammatory capacityof peripheral lymphocytes is predictive of tumor progression and survivaloutcomes in multiple murine models. Specifically, we observed that the quantityof interferon-γ (IFNγ) produced by peripheral lymphocytes in response toCD3/CD28 stimulation was robustly correlated with subsequent survival outcomes.In the tumor models and early time points assessed in this study, thisrelationship was considerably more predictive than a host of other potentialbiomarkers, several of which have been previously reported. Overall, thesefindings suggest that measuring the capacity of peripheral lymphocytes toproduce IFNγ may help identify which patients are benefitting from combinationanti-PD-1/anti-CTLA-4 immunotherapy. Biochemistry (Mosc). 2016Feb;81(2):80-90. doi: 10.1134/S0006297916020024.Interleukins 1and 6 as Main Mediators of Inflammation and Cancer.IL1/IL6是炎性和癌症主要介导者The idea of apotential link between cancer and inflammation was first proposed by R. Virchowin the nineteenth century. However, clear evidence regarding a key role ofinflammation in oncogenesis appeared only during the last decade. Now the tumormicroenvironment is commonly considered as an obligatory and significantcomponent of almost all types of cancer, and the cells infiltrating suchmicroenvironment are a source of inflammatory cytokines. Such cytokines play akey role in regulating inflammation during both normal immune response anddeveloping cancer. In this review, we explore the role of two inflammatorycytokines interleukin 1 and interleukin 6 incancer development. These cytokines have pleiotropic effects on various celltypes in the tumor microenvironment, particularly being able to regulatepro-oncogenic transcription factors NF-κB and STAT3. For this reason, suchcytokines influence key parameters of oncogenesis, increasing cell resistanceto apoptosis, proliferation of cancer cells, angiogenesis, invasion andmalignancy as well as the ability of tumor cells to respond to anticancertherapy. Here we summarize novel experimental data regarding mechanismsunderlying the interaction between chronic inflammation and malignantneoplasms. CellRep. 2016 May 31;15(9):2000-11. doi: 10.1016/j.celrep.2016.04.084. Epub2016 May 19.ReprogrammingTumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progressionand Metastasis.重编码TAMTumors arecomposed of multiple cell types besides the tumor cells themselves, includinginnate immune cells such as macrophages. Tumor-associated macrophages (TAMs) area heterogeneous population of myeloid cells present in the tumormicroenvironment (TME). Here, they contribute to immunosuppression, enablingthe establishment and persistence of solid tumors as well as metastaticdissemination. We have found that the pattern recognition scavenger receptorMARCO defines a subtype of suppressive TAMs and is linked to clinical outcome.An anti-MARCO monoclonal antibody was developed, which induces anti-tumoractivity in breast and colon carcinoma, as well as in melanoma models throughreprogramming TAM populations to a pro-inflammatory phenotype and increasingtumor immunogenicity. This anti-tumor activity is dependent on the inhibitoryFc-receptor, FcγRIIB, and also enhances the efficacy of checkpoint therapy.These results demonstrate that immunotherapies using antibodies designed tomodify myeloid cells of the TME represent a promising mode of cancer treatment. Eur J Cancer.2016 Jul;62:54-61. doi: 10.1016/j.ejca.2016.04.013. Epub 2016 May 20.Targeting ALCAMin the cryo-treated tumour microenvironment successfully induces systemicanti-tumour immunity.低温消融治疗中靶向治疗激活白细胞粘附分子ALCAMCryoablativetreatment has been widely used for treating cancer. However, the therapeuticefficacies are still controversial. The molecular mechanisms of thecryo-induced immune responses, particularly underlying the ineffectiveness,remain to be fully elucidated. In this study, we identified a new molecularmechanism involved in the cryo failure. We used cryo-ineffective metastatictumour models that murine melanoma B16-F10 cells were subcutaneously andintravenously implanted into C57BL/6 mice. When the subcutaneous tumours weretreated cryoablation on day 7 after tumour implantation, cells expressingactivated leucocyte cell adhesion molecule (ALCAM/CD166) were significantlyexpanded not only locally in the treated tumours but also systemically inspleen and bone marrow of the mice. The cryo-induced ALCAM(+) cells includingCD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derivedsuppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantlysuppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) Tcells via ALCAM expressed in these cells. This suggests that systemic expansionof the ALCAM(+) cells negatively switches host-immune directivity to thetumour-supportive mode. Intratumoural injection with anti-ALCAM blockingmonoclonal antibody (mAb) following the cryo treatment systemically inducedtumour-specific CD8(+) T cells with higher cytotoxic activities, resulting insuppression of tumour growth and metastasis in the cryo-resistant tumour models.These suggest that expansion of ALCAM(+) cells is a determinant of limiting thecryo efficacy. Further combination with an immune checkpoint inhibitoranti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combinationtherapy. Targeting ALCAM may be a promising strategy for overcoming the cryoineffectiveness leading to the better practical use of cryoablation in clinicaltreatment of cancer. AnnOncol. 2016 Aug;27(8):1492-504. doi: 10.1093/annonc/mdw217. Epub 2016 May20.Immune escapeto PD-L1/PD-1 blockade: seven steps to success (or failure).Pd-1治疗的免疫逃逸原因The emergence ofprogrammed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)-targeted therapyhas demonstrated the importance of the PD-L1 : PD-1 interaction in inhibitinganticancer T-cell immunity in multiple human cancers, generating durableresponses and extended overall survival. However, not all patients treated withPD-L1/PD-1-targeted therapy experience tumor shrinkage, durable responses, orprolonged survival. To extend such benefits to more cancer patients, it isnecessary to understand why some patients experience primary or secondaryimmune escape, in which the immune response is incapable of eradicating allcancer cells. Understanding immune escape from PD-L1/PD-1-targeted therapy willbe important to the development of rational immune-combination therapy andpredictive diagnostics and to the identification of novel immune targets.Factors that likely relate to immune escape include the lack of strong cancerantigens or epitopes recognized by T cells, minimal activation of cancer-specificT cells, poor infiltration of T cells into tumors, downregulation of the majorhistocompatibility complex on cancer cells, and immunosuppressive factors andcells in the tumor microenvironment. Precisely identifying and understandingthese mechanisms of immune escape in individual cancer patients will allow forpersonalized cancer immunotherapy, in which monotherapy and combinationimmunotherapy are chosen based on the presence of specific immune biology. Thisapproach may enable treatment with immunotherapy without inducing immuneescape, resulting in a larger proportion of patients obtaining clinicalbenefit. Oncotarget.2016 May 17. doi: 10.18632/oncotarget.9391. Theinflammasome: an emerging therapeutic oncotarget for cancer prevention.炎性体新癌症治疗靶点Deregulatedinflammation is considered to be one of the hallmarks of cancer initiation anddevelopment regulation. Emerging evidence indicates that the inflammasome playsa central role in regulating immune cells and cytokines related to cancer. Theinflammasome is a multimeric complex consisting of Nod-like receptors (NLRs)and responds to a variety of endogenous (damage-associated molecular patterns)and exogenous (pathogen-associated molecular patterns) stimuli. Several linesof evidence suggests that in cancer the inflammasome is positively associatedwith characteristics such as elevated levels of IL-1β and IL-18, activation ofNF-κB signaling, enhanced mitochondrial oxidative stress, and activation ofautophagic process. A number of NLRs, such as NLRP3 and NLRC4 are alsohighlighted in carcinogenesis and closely correlate to chemoresponse andprognosis. Although conflicting evidence suggested the duplex role ofinflammasome in cancer development, the phenomenon might be attributed to NLRsdifference, cell and tissue type, cancer stage, and specific experimentalconditions. Given the promising role of inflammasome in mediating cancerdevelopment, precise elucidation of its signaling network and pathologicalsignificance may lead to novel therapeutic options for malignancy therapy andprevention. Oncotarget.2016 May 18. doi: 10.18632/oncotarget.9438. Sorafenibinhibits macrophage-mediated epithelial-mesenchymal transition inhepatocellular carcinoma.Tumor-associatedmacrophages, crucial components of the microenvironment in hepatocellularcarcinoma, hamper anti-cancer immune responses. The aim of the present studywas to investigate the effect of sorafenib on the formation of the tumormicroenvironment, especially the relationship between polarized macrophages andhepatocytes. Macrophage infiltration was reduced in patients withhepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenibabolished polarized macrophage-induced epithelial mesenchymal transition (EMT)and migration of hepatocellular carcinoma cells but not normal hepatocytes.Moreover, sorafenib attenuated HGF secretion in polarized macrophages, anddecreased plasma HGF in patients with hepatocellular carcinoma. Additionally,sorafenib abolished the polarized macrophage-induced activation of the HGFreceptor Met in hepatocellular carcinoma cells. Our findings suggest thatsorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinomacells via the HGF-Met signaling pathway. These results contribute to ourunderstanding of the immunological mechanisms that underlie the protectiveeffects of sorafenib in hepatocellular carcinoma therapy. MolTher. 2016 Jun 14. doi: 10.1038/mt.2016.106. TranslationalImplications for Off-the-shelf Immune Cells Expressing Chimeric AntigenReceptors.Chimeric antigenreceptor (CAR) endows specificity to T-cells independent of human leukocyteantigen (HLA). This enables one immunoreceptor to directly target the samesurface antigen on different subsets of tumor cells from multiple HLA-disparaterecipients. Most approaches manufacture individualized CAR+T-cellsfrom the recipient or HLA-compatible donor, which are revealing promisingclinical results. This is the impetus to broaden the number of patientseligible to benefit from adoptive immunotherapy such as to infuse third-partydonor derived CAR+T-cells. This will overcome issues associated with(i) time to manufacture T-cells, (ii) cost to generate one product for onepatient, (iii) inability to generate a product from lymphopenic patients orpatient's immune cells fail to complete the manufacturing process, and (iv)heterogeneity of T-cell products produced for or from individual recipients.Establishing a biobank of allogeneic genetically modified immune cells fromhealthy third-party donors, which are cryopreserved and validated in advance ofadministration, will facilitate the centralizing manufacturing and widespreaddistribution of CAR+T-cells to multiple points-of-care in a timelymanner. To achieve this, it is necessary to engineer an effective strategy toavoid deleterious allogeneic immune responses leading to toxicity andrejection. We review the strategies to establish "off-the-shelf"donor-derived biobanks for human application of CAR+T-cells as adrug.Molecular Therapy (2016); Front Cell Neurosci. 2016 May2;10:109. doi: 10.3389/fncel.2016.00109. eCollection 2016.ExtracellularVesicles in Physiology, Pathology, and Therapy of the Immune and CentralNervous System, with Focus on Extracellular Vesicles Derived from MesenchymalStem Cells as Therapeutic Tools.胞外囊泡Extracellularvesicles (EVs) are membrane-surrounded structures released by most cell types.They are characterized by a specific set of proteins, lipids and nucleic acids.EVs have been recognized as potent vehicles of intercellular communication to transmitbiological signals between cells. In addition, pathophysiological roles of EVsin conditions like cancer, infectious diseases and neurodegenerative disordersare well established. In recent years focus has been shifted on therapeutic useof stem cell derived-EVs. Use of stem cell derived-EVs present distinctadvantage over the whole stem cells as EVs do not replicate and afterintravenous administration, they are less likely to trap inside the lungs. Fromthe therapeutic perspective, the most promising cellular sources of EVs aremesenchymal stem cells (MSCs), which are easy to obtain and maintain.Therapeutic activity of MSCs has been shown in numerous animal models and thebeneficial paracrine effect of MSCs may be mediated by EVs. The various componentsof MSC derived-EVs such as proteins, lipids, and RNA might play a specifictherapeutic role. In this review, we characterize the role of EVs in immune andcentral nervous system (CNS); present evidences for defective signaling ofthese vesicles in neurodegeneration and therapeutic role of EVs in CNS. 英文太多，要是都翻译成中文就好了 楼主真不容易，找了这么多资料
页:
[1]