The Importance of T cell Survival in Tumor Immunity

在癌症患者中加强基于免疫的策略的一个关键组成部分是增加 肿瘤特异性效应T细胞的存活(S)，这导致肿瘤特异性记忆增强。在……里面 携带肿瘤的宿主维持高水平的肿瘤抗原特异性T细胞很重要，因为这很难 消灭所有的肿瘤细胞。从本质上讲，这造成了肿瘤细胞和 免疫系统，而免疫系统的胜利对于宿主的生存至关重要。学习如何给小费 有利于效应T细胞存活的平衡将是增强癌症免疫的重要策略。 有气质的个体。最近的一项临床试验极大地提高了过继转移肿瘤的存活率 癌症患者中银特异的T细胞，这种T细胞存活率的增加与临床的增加相关 回应。因此，了解T细胞生存途径所涉及的机制对于 开发旨在增强癌症患者肿瘤免疫的新策略。 我们小组一直在研究肿瘤坏死因子受体家族成员OX40的生物学功能，它已经 我们的团队和其他人已经证明了提高CD4和CDS T细胞的存活率，从而增加记忆力。 特别是，我们已经证明OX40与荷瘤宿主的接触增强了抗肿瘤免疫 导致肿瘤的破坏。我们发现，通过OX40接触治愈肿瘤的小鼠有 肿瘤特异性记忆性T细胞过继转移可诱导抗肿瘤免疫 天真的老鼠。因此，我们建议研究抗OX40介导的T细胞的作用机制(S) 荷瘤宿主的存活率进一步了解肿瘤抗原特异性T细胞增加之间的联系 存活率和免疫介导性治疗效果。拨款申请的具体目的如下： 1)了解IL-12在抗OX40增强肿瘤特异性T细胞记忆中的作用，2) 阐明抗OX40增强CD4和CDS T细胞存活的分子基础；3) 确定临床上相关的方法来诱导抗OX40和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有助于我们 设计更有效的方法来加强肿瘤免疫治疗，并最终获得更多的了解 抗OX40特异性疗法。OX40特异的免疫系统增强作用最近在 相关性，因为我们已经生产出临床级别的抗OX40抗体，并治疗了前三种癌症 作为I期临床试验的一部分，携带这种抗体的患者。

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 CDS 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 CDS 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.