Oxidative stress and AICD in memory T cell persistence

描述（由申请人提供）：CD 8 + T细胞通过活化、分裂和分化过程对抗原刺激作出应答，以产生大量活化的效应细胞溶解性T淋巴细胞（CTL）。许多癌症患者体内都含有前体CTL，可以被激活以响应许多“自身”肿瘤相关表位。在某些情况下，用这些表位中的一些接种疫苗可以诱导抗肿瘤应答。然而，已经确定了肿瘤发展以成功逃避宿主免疫系统的各种分子和细胞机制。这些机制中的一些靶向抗肿瘤效应CTL，其不能通过仅旨在激活抗肿瘤免疫应答的免疫疗法来校正。我们的初步数据表明，效应记忆表型轴承T细胞成为优先功能障碍的条件下，外源性氧化应激，但也经历了增加激活诱导的细胞死亡（AICD）的抗原相遇。在经历AICD的CTL中可以看到增加的超氧化物产生，其可以通过用超氧化物歧化酶模拟物MnTBAP预处理来拯救。基于我们的初步数据，我们假设，记忆T细胞亚群之间的差异氧化还原状态调节对AICD或凋亡的敏感性。使用MART-127-35表位特异性人CTL和来自我们的新型转基因h3 T小鼠的T细胞，所述小鼠在CD 4+和CD 8 + T细胞上携带HLA-A2限制性酪氨酸特异性功能性TCR，我们提出进行以下：1）为了确定T细胞亚群的差异氧化还原状态是否（TCM vs. TEM）通过影响内在信号分子调节对氧化应激诱导的凋亡和AICD的敏感性。2)确定差异调节氧化应激介导的凋亡和记忆T细胞亚群的AICD的外在因素（TCM与TEM）;和3）建立用于评估抗氧化剂处理的T细胞或抗氧化酶转导的T细胞在肿瘤消退、持久性和记忆中的体内模型。我们相信，成功完成所提出的工作将有助于确定可用于改善接受过继性T细胞治疗癌症患者的效应CTL存活率和长期记忆发育的靶点。 公共卫生相关性：尽管由癌症疫苗激活的T淋巴细胞实际上能够攻击和破坏肿瘤细胞，但它们在控制肿瘤消退方面无效的原因一直令人困惑。我们的数据表明，它是氧化应激和抗原介导的优先死亡的抗原经历/记忆表型轴承CTL，可能会导致功能不足。由于CTL的持续性是影响任何免疫治疗方案结果的重要因素，我们认为通过鉴定和靶向途径来保护效应淋巴细胞以拯救CTL免于过早死亡，可以显著改善其抗肿瘤效果。

DESCRIPTION (provided by applicant): CD8+ T cells respond to antigen stimulation through a process of activation, division, and differentiation to generate a large pool of activated effector cytolytic T lymphocytes (CTL). Many cancer patients harbor precursor CTL that can be activated to respond to many "self" tumor-associated epitopes. Vaccination with some of these epitopes can induce anti-tumor responses in some cases. However, various molecular and cellular mechanisms that tumors develop to successfully evade the host immune system have been identified. Some of these mechanisms target anti-tumor effector CTL that cannot be corrected by immunotherapy aimed only at activation of anti-tumor immune responses. Our preliminary data shows that effector memory phenotype bearing T cell becomes preferentially dysfunctional under conditions of exogenous oxidative stress but also undergo increased activation induced cell death (AICD) on antigenic encounter. Increased superoxide production can be seen in CTL undergoing AICD that can be rescued by pretreatment with superoxide dismutase mimetic MnTBAP. Based on our preliminary data we hypothesize that differential redox status between memory T cell subsets regulates the sensitivity towards AICD or apoptosis. Using MART-127-35 epitope specific human CTL and T cells from our novel transgenic h3T mouse that carries HLA-A2 restricted tyrosine specific functional TCR on both CD4+ and CD8+ T cells we propose to carry out the following: 1) To determine if differential redox state of the T cell subsets (TCM vs. TEM) regulates sensitivity to oxidative stress induced apoptosis and AICD by effecting intrinsic signaling molecules.; 2) To determine extrinsic factors that differentially regulate oxidative stress mediated apoptosis and AICD of memory T cell subsets (TCM vs. TEM); and 3) To establish an in vivo model for evaluation of antioxidant treated T cells or antioxidant enzyme transduced T cells in tumor regression, persistence and memory. We believe that successful completion of the proposed work would help identify targets that could be used to improve survival of effector CTL and long-term memory development in patients receiving adoptive T cell therapy for cancer. PUBLIC HEALTH RELEVANCE: Despite T lymphocytes activated by cancer vaccination are virtually competent to attack and destroy neoplastic cells, the reason for their inefficacy in controlling tumor regression has been puzzling. Our data shows that it is both oxidative stress and antigen mediated preferential death of antigen-experienced/memory phenotype bearing CTL that might result in inadequate function. Since persistence of CTL is an important factor that affects the outcome of any immunotherapy protocol we believe that protecting effector lymphocytes by identifying and targeting the pathways to rescue CTL from premature death, their anti-tumor effect could be substantially improved.