Effector T Cell Trafficking in Ovarian Cancer

 描述（由申请方提供）：效应T细胞介导保护性肿瘤免疫。肿瘤免疫治疗包括检查点阻断、免疫接种和过继效应T细胞等，其目的是产生长期保护性效应T细胞免疫，使肿瘤患者产生肿瘤放射。为此，效应T细胞必须进入并保留在肿瘤微环境中。有趣的是，肿瘤免疫学领域的核心科学工作集中在探索，设计和确定效应T细胞的功能效力和治疗功效。然而，我们目前的知识效应T细胞肿瘤的运输和保留，其潜在的分子机制仍然知之甚少的癌症患者。这种无意的缺陷显着缓和我们的努力，了解基本的人类效应T细胞生物学，建立和评估免疫治疗方案和肿瘤疫苗治疗癌症患者。对效应T细胞肿瘤在人类肿瘤微环境中运输的性质进行全面的分子和功能研究是至关重要的。Th1型趋化因子CXCL9和CXCL10介导效应T细胞迁移。CXCL9和CXCL10已被证明与人类肿瘤中的T细胞密度相关，并且与癌症患者存活率正相关。众所周知，IFNγ在多种细胞中刺激CXCL9和CXCL10的产生。然而，人们对Th1型趋化因子在人类癌症微环境中的表达是如何调节的，以及效应T细胞肿瘤运输是如何控制的知之甚少。包括组蛋白修饰在内的表观遗传沉默是肿瘤发生的重要机制。然而，其在肿瘤免疫中的作用仍有待确定。以人原发性卵巢癌为模型，我们的初步研究表明，多梳复合物2（PRC2）蛋白，基于zeste 2（EZH2）的组蛋白H3赖氨酸27三甲基化（H3K27me3）的增强子选择性地参与调节Th1型趋化因子CXCL9和CXCL10的肿瘤产生，并可能随后决定效应T细胞运输到肿瘤微环境。基于这一令人惊讶的新发现，我们假设肿瘤表观遗传沉默不仅是一个重要的致癌机制，而且是控制Th1型趋化因子表达的关键电路，从而影响效应T细胞肿瘤运输和肿瘤治疗。我们提出了两个具体的目标，机械，功能和临床测试我们的中心假设。目的1是验证我们的假设，PRC2信号通路 控制肿瘤微环境中Th1型趋化因子的产生。目的2是验证我们的假设，PRC2信号通路在临床和治疗上与效应T细胞肿瘤运输和肿瘤免疫相关。

 DESCRIPTION (provided by applicant): Effector T cells mediate protective tumor immunity. The goal of tumor immune therapy including check-point blockade and immune vaccination and adoptive effector T cell is to engender long-term protective effector T cell immunity, and cause tumor eradiation in patients with cancer. To this end, effector T cells must traffic into and retai within the tumor microenvironment. Interestingly, the central scientific efforts in the field of tuor immunology are focused on exploring, designing and determining the functional potency and therapeutic efficacy of effector T cells. However, our current knowledge of effector T cell tumor trafficking and retention, and its underlying molecular mechanisms remain poorly understood in patients with cancer. This inadvertent deficiency significantly tempers our efforts toward understanding basic human effector T cell biology, establishing and evaluating immune therapeutic regimens and tumor vaccines in treating patients with cancer. It is essential to conduct comprehensive molecular and functional research on the nature of effector T cell tumor trafficking in the human tumor microenvironment. Th1-type chemokines CXCL9 and CXCL10 mediate effector T cell migration. CXCL9 and CXCL10 have been shown to be correlated with T cell density in human tumor and are associated positively with cancer patient survival. It is well known that IFNγ stimulates the production of CXCL9 and CXCL10 in variety of cells. However, it is poorly understood how Th1-type chemokine expression is regulated in the human cancer microenvironment, and in turn how effector T cell tumor trafficking are controlled. Epigenetic silencing including histone modifications is important tumorigeneic mechanism in cancer. However, its role in tumor immunity remains to be defined. Using human primary ovarian cancer as a model, our preliminary studies demonstrated that a polycomb complex 2 (PRC2) protein, enhancer of zeste 2 (EZH2)-based histone H3 lysine 27 trimethylation (H3K27me3) was selectively involved in the regulation of the tumor production of Th1-type chemokines CXCL9 and CXCL10, and might subsequently determine effector T cell trafficking to the tumor microenvironment. Based on this surprising and novel finding, we hypothesize that tumor epigenetic silencing is not only a crucial carcinogeneic mechanism, but also key circuits controlling Th1-type chemokine expression and consequently impact effector T cell tumor trafficking and tumor therapy. We propose two specific aims to mechanistically, functionally and clinically test our central hypothesis. Aim 1 is to test our hypothesis that PRC2-signaling circuit controls Th1-type chemokine production in the tumor microenvironment. Aim 2 is to test our hypothesis that PRC2-signaling circuit clinically and therapeutically associates with effector T cell tumor trafficking and tumor immunity.