The Importance of T cell Survival in Tumor Immunity

描述(申请人提供)：在携带肿瘤的个体中增强基于免疫的策略的一个关键组件是增加肿瘤特异性效应T细胞的存活率(S)，这会导致肿瘤特异性记忆的增强。在携带肿瘤的宿主中，维持高水平的肿瘤抗原特异性T细胞是很重要的，因为很难消除每一个肿瘤细胞。从本质上讲，这在肿瘤细胞和免疫系统之间造成了一场持续的战斗，免疫系统获胜对于宿主的生存至关重要。学习如何扭转平衡，有利于效应T细胞的生存，将是提高癌症患者免疫力的重要策略。最近的一项临床试验极大地提高了癌症患者过继转移的肿瘤抗原特异性T细胞的存活率，这种T细胞存活率的增加与临床反应的增加相关。因此，了解T细胞存活途径涉及的机制对于开发旨在增强癌症患者肿瘤免疫的新策略至关重要。我们团队一直在研究肿瘤坏死因子受体家族成员OX40的生物学功能，我们的团队和其他人已经证明OX40可以提高CD4和CD8 T细胞的存活率，从而增加记忆力。特别是，我们已经证明了OX40与荷瘤宿主的接触增强了抗肿瘤免疫，从而导致了肿瘤的破坏。我们发现，通过OX40结合治愈肿瘤的小鼠具有肿瘤特异性记忆T细胞，通过过继转移到幼小鼠中能够激发强大的抗肿瘤免疫。因此，我们建议研究抗氧合酶40介导的T细胞在荷瘤宿主中存活的机制(S)，以进一步了解肿瘤抗原特异性T细胞存活增加与免疫介导的治疗效果之间的联系。拨款申请的具体目的如下：1)了解IL-12对抗OX40增强肿瘤特异性T细胞记忆的贡献；2)阐明抗OX40增强CD4和CD8 T细胞存活的分子基础；3)确定临床相关方法，以诱导抗OX40与天然细胞因子之间的协同作用，以增强肿瘤特异性T细胞记忆和肿瘤的破坏。从这笔赠款中获得的知识将帮助我们设计更有效的方法来加强肿瘤免疫治疗，并最终获得对抗OX40特异性治疗的更多了解。最近，OX40特异性免疫系统的增强作用有所增加，因为我们已经生产出临床级别的抗OX40抗体，并作为I期临床试验的一部分，用这种抗体治疗了前三名癌症患者。

DESCRIPTION (provided by applicant): A key component to enhance immune-based strategies in cancer-bearing individuals is to increase the survival of effector T cells specific for tumor Ag(s), which leads to increased tumor-specific memory. In cancer-bearing hosts it is important to maintain high levels of tumor Ag-specific T cells, because it is difficult to eliminate every last tumor cell. In essence this creates an ongoing battle between the tumor cells and the immune system and it is essential that the immune system win for the host to survive. Learning how to tip the balance in favor of effector T cell survival will be an important strategy for enhancing immunity in cancer- bearing individuals. A recent clinical trial dramatically increased the survival of adoptively transferred tumor Ag-specific T cells in cancer patients and this increase in T cell survival correlated with increased clinical responses. Thus, understanding the mechanisms involved in the T cell survival pathway is crucial to developing new strategies aimed at potentiating tumor immunity in cancer patients. Our group has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by our group and others to enhance CD4 and CD8 T cell survival leading to increased memory. In particular, we have shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. We have found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naive mice. Therefore we propose to study the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy. The specific aims of the grant application are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CD8 T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this grant will help us design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 antibody and treated the first three cancer patients with this antibody as part of a phase I clinical trial.