Novel Targets for Protection of T Cells From Tumor-Induced Dysfunction

描述（由申请人提供）：卵巢癌是癌症死亡的主要原因。化疗在减少大多数患者的肿瘤负担方面是有效的，然而，只有大约20%的晚期疾病患者最终将无肿瘤生存，并且需要进一步的治疗选择。免疫学的不断进步使免疫治疗成为当前和未来研究的一个活跃领域。然而，卵巢癌免疫治疗策略的设计需要了解腹腔的免疫微环境，这是发生最具破坏性影响的部位。越来越多的证据表明，凋亡性死亡和对凋亡的敏感性增强参与了肿瘤微环境中T淋巴细胞的功能障碍。癌症患者免疫治疗方法的未来成功取决于对肿瘤部位T细胞的保护及其效率的提高。Mcl-1是Bcl-2家族的一个成员，最近被证明是成熟T淋巴细胞存活所必需的。我们的初步结果表明，Mcl-1在保护T淋巴细胞免受肿瘤诱导的凋亡中具有关键的调节作用，该凋亡是通过Bim和p53介导的。在促存活Bcl-2家族成员中，Mcl-1是响应于T细胞稳态细胞因子IL-2、IL-7、IL-12和IL-15而经历显著上调表达的主要蛋白质。本申请将试图阐明Mcl-1在肿瘤微环境中保护OvCA相关淋巴细胞免于凋亡死亡的作用和功能机制。潜在的科学方法将Mcl-1和Bim或p53之间交叉调节性质的基本分子分析与利用这些分子作为改善OvCA当前免疫方案的靶点的翻译组分相结合。

DESCRIPTION (provided by applicant): Ovarian cancer is a leading cause of cancer mortality. Chemotherapy is effective in reducing tumor burden in a majority of patients, however, only approximately 20% of advanced disease patients will ultimately survive tumor-free, and further treatment options are needed. Continuing advances in immunology make immunotherapy an active area for current and future research. However, the design of immunotherapeutic strategies for ovarian cancer requires an understanding of the immune microenvironment of the peritoneal cavity, the site where the most devastating effects occur. Evidence is accumulating to suggest that apoptotic death and enhanced susceptibility to apoptosis are involved in the dysfunction of T lymphocytes at the tumor microenvironment. Future success of immunotherapeutic approaches for cancer patients are dependent on the protection of T cells at the tumor site and the enhancement of their efficiency. Mcl-1, a prosurvival Bcl-2 family member has recently been demonstrated to be required for the survival of mature T lymphocytes. Our preliminary results suggest that Mcl-1 has a key regulatory role in the protection of T lymphocytes from tumor-induced apoptosis that is mediated through Bim and p53. Among the pro-survival Bcl-2 family members, Mcl-1 is the major protein to undergo significant upregulated expression in response to T-cell homeostasis cytokines, IL-2, IL-7, IL-12 and IL-15. The current application will attempt to elucidate the role and functional mechanisms of Mcl-1 in the protection of OvCA-associated lymphocytes from apoptotic death at the tumor microenvironment. The underlying scientific approach combines a basic molecular analysis of the nature of cross-regulation between Mcl-1 and Bim or p53 with a translational component that utilizes these molecules as targets for the improvement of current immunotherapeutic protocols for OvCA.