Cbl-b基因在外周血CD8^＋T细胞抗肿瘤免疫中的作用

Cbl-b（casitas B cell lymphoma-b）基因是cb1家族成员,其编码的蛋白与信号转导蛋白相互作用,在调节抗肿瘤免疫方面发挥着重要作用。通过基因干扰技术沉默机体外周血T细胞cbl-b基因的表达从而调节机体的抗肿瘤免疫有望在肿瘤治疗上实现重大突破。     

Cbl-b 基因在外周血 CD8~+T 细胞抗肿瘤免疫中的作用

Cbl-b( casitas B cell lymphoma-b )基因是cbl家族成员,其编码的蛋白与信号转导蛋白相互作用,在调节抗肿瘤免疫方面发挥着重要作用.通过基因干扰技术沉默机体外周血T细胞 Cbl-b 基因的表达从而调节机体的抗肿瘤免疫有望在肿瘤治疗上实现重大突破.     

调节性T细胞在肿瘤免疫和肿瘤免疫治疗中的作用

肿瘤局部存在多种类型的免疫抑制性细胞,其中调节性T细胞 (regulatory T cell,Treg)在肿瘤的发生、发展过程中发挥着极为重要的作用。Treg通过多种机制抑制免疫效应细胞的功能,是肿瘤免疫逃逸的关键因素。这些机制包括分泌抑制性细胞因子抑制效应细胞功能、分泌颗粒酶和穿孔素杀伤效应细胞、干扰效应细胞的代谢功能,以及通过调控树突状细胞影响Treg的分化和增殖,等等。Treg的深入研究为肿瘤免疫治疗提供了新的思路,以Treg及相关免疫抑制性分子作为靶点,通过特异性或非特异性清除Treg、控制Treg的数量和功能等开展肿瘤免疫治疗具有良好的临床应用前景。     

树突状细胞在食管癌T细胞抗肿瘤免疫中的作用

目的：研究食管癌组织中树突状细胞（ＤＣｓ）在肿瘤浸润性Ｔ淋巴细胞激活中的作用,方法：用免疫组化和ＲＴ－ＰＣＲ的方法,检测４６例食管癌手术标本中ＤＣｓ（ＣＤ１ａ）、Ｔ细胞亚群（ＣＤ３、ＣＤ４、Ｃ人刺激因子Ｂ７。结果：癌组织中的ＤＣｓ与ＣＤ３（＋）、ＣＤ４（＋）Ｔ细胞有相关性,与ＣＤ８（＋）、ＣＤ２５（＋）Ｔ细胞无明显关系,且Ｂ７ｍＲＮＡ表达均为阴性,结论：食管癌中ＤＣｓ不一定能有效地激活Ｔ细胞,其中Ｂ７基因表达受抑制,可能是不能有效激活Ｔ淋巴细胞产生免疫耐受的重要原因之一。     

T淋巴细胞在肿瘤免疫中的双重作用及其免疫治疗现状

摘 要：肿瘤免疫治疗作为一种新的手段取得了备受瞩目的临床疗效,在晚期肿瘤中甚至可以达到临床治愈。T细胞亚群作为机体细胞免疫功能的重要组成部分,在抗肿瘤免疫及肿瘤免疫逃避中均发挥着十分重要的作用。全文就T细胞亚群的生物学特性、在肿瘤免疫激活及肿瘤免疫逃避中的作用和机制及相关肿瘤免疫治疗研究进展作一综述。     

肿瘤免疫治疗与肿瘤特异记忆性T细胞

近年来以肿瘤相关抗原(TAA)及树突状细胞(DC)呈递机制为基础发展起来的肿瘤免疫治疗取得一定进展，研究表明，肿瘤特异记忆性T细胞存在于患者骨髓中，体内外实验均证实其再激活后对肿瘤靶细胞具有更有效的杀伤作用。     

肿瘤浸润调节性T细胞生物学特性及调节性T细胞在肿瘤免疫治疗中的应用

调节性T细胞（Treg细胞）对机体内环境稳定至关重要。然而,肿瘤浸润Treg细胞（TITR）在肿瘤微环境（TME）中发挥免疫抑制作用,削弱抗肿瘤特异性免疫应答,从而促进肿瘤逃避免疫监视。近来,随着免疫检查点抑制剂、趋化因子及其受体阻断剂、Treg细胞选择性靶点敲除和新药的问世,基于Treg细胞的肿瘤免疫治疗取得了较好的...     

基于记忆性干性T细胞和中心记忆性T细胞的细胞免疫治疗在血液肿瘤治疗中的价值

近年来,以抗原嵌合受体T细胞(CAR-T)为代表的细胞免疫治疗在血液肿瘤治疗中取得重大突破.记忆性干性T细胞(Tb)和中心记忆性T细胞(TCM)是T细胞免疫治疗强有力的载体,如何在体内及体外调控该类细胞的分化、如何利用其构建强效的治疗系统而避免潜在的毒副作用受到研究者们的关注.文章主要总结了第58届美国血液学会(ASH)年会关于TSCM和TCM在血液肿瘤治疗中的价值和相关研究进展.     

调节性T细胞诱导肿瘤免疫耐受的机制

调节性T细胞(Treg)是一类免疫抑制性T辅助(Th)细胞.研究表明,Treg可在肿瘤细胞分泌的趋化因子CCL22作用下大量募集于肿瘤周围,分泌或表达免疫抑制性的细胞因子和受体,形成以Th2型免疫为主的微环境,引导宿主免疫耐受.通过抗体等药物降低Treg数量和活性后可打破肿瘤免疫耐受,抑制肿瘤的发生和转移.     

免疫微环境介导的肿瘤耐受机制及其靶向治疗

免疫细胞与其分泌的细胞因子相互作用共同构成免疫微环境,在肿瘤治疗耐受过程中扮演着重要角色.免疫微环境能够通过启动抗凋亡通路、介导免疫耐受、诱导上皮间质转化及形成肿瘤干细胞等途径促进肿瘤产生治疗耐受,降低肿瘤治疗疗效.肿瘤免疫治疗已成为目前肿瘤治疗研究领域的热点.     

T细胞凋亡在肿瘤免疫逃避中的作用

肿瘤细胞通过多种途径引起肿瘤反应性T细胞凋亡是肿瘤实现免疫逃避的重要机制之一,现总结肿瘤免疫中T细胞凋亡的证据、实现途径和细胞信号传导机制的研究进展.     

吲哚胺2,3双加氧酶与肿瘤免疫耐受

调节性T细胞(Treg)介导的克隆抑制,是引起肿瘤免疫耐受的主要因素之一.而吲哚胺2,3双加氧酶(IDO)通过对Treg细胞的作用下调各系统肿瘤微环境中的免疫反应,从而诱导宿主免疫耐受的形成.IDO抑制剂1-MT将有望成为治疗肿瘤的新靶点.     

Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation

Cbl-b, a mammalian homolog of Cbl, consists of an N-terminal region (Cbl-b-N) highly homologous to oncogenic v-Cbl, a Ring finger, and a C-terminal region containing multiple proline-rich stretches and potential tyrosine phosphorylation sites. In the present study, we demonstrate that upon engagement of the T cell receptor (TCR), endogenous Cbl-b becomes rapidly tyrosine-phosphorylated. In heterogeneous COS-1 cells, Cbl-b was phosphorylated on tyrosine residues by both Syk- (Syk/Zap-70) and Src- (Fyn/Lck) family kinases, with Syk kinase inducing the most prominent effect. Syk associates and phosphorylates Cbl-b in Jurkat T cells. A Tyr-316 Cbl-binding site in Syk was required for the association with and for the maximal tyrosine phosphorylation of Cbl-b. Mutation at a loss-of-function site (Gly-298) in Cbl-b-N disrupts its interaction with Syk. Cbl-b constitutively binds Grb2 and becomes associated with Crk-L upon TCR stimulation. The Grb2- and the Crk-L-binding regions were mapped to the C-terminus of Cbl-b. The Crk-L-binding sites were further determined to be Y655DVP and Y709KIP, with the latter being the primary binding site. Taken together, these results implicate that Cbl-b is involved in TCR-mediated intracellular signaling pathways.     

吲哚胺2，3-双加氧酶与肿瘤免疫耐受

人体免疫系统可以对肿瘤表达的多种异常抗原产生免疫反应,但肿瘤通过复杂的进化过程所致的免疫耐受现象能够降低宿主针对肿瘤的自身免疫反应,使宿主无法通过免疫系统对肿瘤细胞作出免疫应答。因此该现象可导致肿瘤细胞逃避宿主的免疫监视以及免疫系统的攻击,从而使肿瘤细胞得以在人体内增殖和转移。IDO是细胞内催化L-色氨酸经犬尿氨酸途径进行分解代谢的关键酶,也是一种与免疫抑制相关的酶。IDO在多种病理生理过程中促进机体免疫耐受的发生,因此与肿瘤的发生发展有密切关系。大量研究发现,IDO作为一种重要的抑制性免疫检查点,在肿瘤患者中其酶活性的增加会促进肿瘤免疫耐受现象的建立。随着IDO介导肿瘤免疫耐受相关分子机制的发现与证实,IDO抑制剂也已成为肿瘤免疫疗法中的关键研究领域。本文重点阐明IDO发现的起源过程、在正常人体和肿瘤患者中的表达情况、调节色氨酸代谢等免疫调节功能以及IDO诱导TME中肿瘤免疫耐受建立的几种重要机制,包括色氨酸耗竭、激活芳香烃受体、诱导调节性T细胞扩增与活化以及募集和激活大量骨髓来源的抑制性细胞等机制,以便能够为今后的深入研究和IDO抑制剂的治疗应用提供更广阔的思维。     

Role of the tumor immune microenvironment in tumor immunotherapy

Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.     

Generation of T cell effectors using tumor cell-loaded dendritic cells for adoptive T cell therapy

Adoptive T cell transfer has been shown to be an effective method used to boost tumor-specific immune responses in several types of malignancies. In this study, we set out to optimize the ACT protocol for the experimental treatment of prostate cancer. The protocol includes a pre-stimulation step whereby T cells were primed with autologous dendritic cells loaded with the high hydrostatic pressure-treated prostate cancer cell line, LNCaP. Primed T cells were further expanded in vitro with anti-CD3/CD28 Dynabeads in the WAVE bioreactor 2/10 system and tested for cytotoxicity. Our data indicates that the combination of pre-stimulation and expansion steps resulted in the induction and enrichment of tumor-responsive CD4⁺ and CD8⁺ T cells at clinically relevant numbers. The majority of both CD4⁺ and CD8⁺ IFN-γ producing cells were CD62L, CCR7 and CD57 negative but CD28 and CD27 positive, indicating an early antigen experienced phenotype in non-terminal differentiation phase. Expanded T cells showed significantly greater cytotoxicity against LNCaP cells compared to the control SKOV-3, an ovarian cancer line. In summary, our results suggest that the ACT approach together with LNCaP-loaded dendritic cells provides a viable way to generate prostate cancer reactive T cell effectors that are capable of mounting efficient and targeted antitumor responses and can be thus considered for further testing in a clinical setting.     

CIK细胞治疗对肿瘤患者外周血免疫细胞亚型的影响

目的： 分析接受细胞因子诱导的杀伤（cytokine-induced killer,CIK）细胞治疗后肿瘤患者外周血免疫细胞亚型的变化,探讨CIK细胞治疗对肿瘤患者免疫功能的影响。 方法： 采集2012年3月7日至2012年8月30日期间河北医科大学第四医院生物治疗科收治的60例肿瘤患者（肺癌25例、胃癌8例、直肠癌6例、食管癌11例、黑素瘤7例和乳腺癌3例）外周血及对照组20名健康志愿者外周血,分离外周血单个核细胞,常规方法体外扩增CIK细胞,分3次回输患者体内,流式细胞术检测CIK细胞治疗前后肿瘤患者外周血淋巴细胞亚型的变化。 结果： 与治疗前相比,经1次CIK细胞治疗后,CD3+CD4+T细胞比例升高（P=0.016）、CD4+/CD8+细胞比值升高（P=0.013）且均达到正常水平,CD3+CD8+细胞比例降低（P=0109）但仍高于对照组（P=0.048);3次CIK细胞治疗后相比1次治疗后无显著变化（P>0.05）。CD4+CD25+Treg比例经1次CIK治疗后较治疗前显著下降（P=0.007）,达到正常水平;3次治疗后持续下降（P=0.005）。CIK治疗对CD3-CD19+B细胞和CD3-CD56+自然杀伤（natural killer,NK）细胞水平无显著影响（P>0.05）。 结论： CIK细胞治疗能够降低肿瘤患者外周血Treg比例,升高CD3+CD4+T细胞比例及CD4+/CD8+细胞比值,从而减轻或消除肿瘤患者的免疫抑制状态。