Ovarian Cancer Epigenetics, Immunity and Therapy

以Th1型趋化因子(如CXCL9和CXCL10)表达有限和频率低为特征的肿瘤 效应肿瘤浸润性淋巴细胞(TIL)在微环境中的作用，呈现免疫细胞靶向方案 不太可能成功。在高级别浆液性卵巢癌患者中，多梳抑制复合体2 组蛋白H3赖氨酸27三甲基化(H3K27me3)介导组蛋白H3赖氨酸27三甲基化 抑制CXCL9和CXCL10的表达。它控制着效应器T细胞肿瘤的运输和影响 肿瘤免疫治疗的疗效。因此，表观遗传机制(如PRC2)可能控制 “热”与“冷”的癌症表型及免疫治疗效果的比较。 除了PRC2，哺乳动物染色质重塑开关/蔗糖不可发酵(SWI/SNF)复合体 BAF复合体(又称BAF复合体，即Brg/Brama相关因子复合体)是重要的表观遗传机制。在… - 富含相互作用结构域的蛋白1A(ARID1A)是SWI/SNF复合体的一员。潜力 免疫学作用、免疫调节机制、免疫相关临床意义 治疗方面的相关性 ARID1A 在包括卵巢癌在内的人类癌症中是未知的。 我们的 初步数据显示，在几个突变的卵巢透明细胞中，干扰素γ信号通路存在缺陷 完整的CXCL9和CXCL10的表达需要癌细胞和ARID1A。我们之前的工作揭示了 PRC2复合体抑制CXCL9和CXCL10在高级别卵巢癌中的表达因此，我们 假设PRC2(例如EZH2)和SWI/SNF(例如ARID1A)之间可能存在动态平衡 复合体在控制卵巢癌干扰素γ反应性中的作用。为了验证这一假设，我们的项目是 对效应器T的性质进行全面的分子、功能、翻译和临床研究 在人卵巢癌微环境中的细胞肿瘤转移和干扰素γ途径，并将提供 丰富的机会将我们对肿瘤效应T细胞生物学的了解提高到一个新的基础和水平 实际应用。该应用程序具有很强的翻译性。我们的具体目标是： 目标1是测试我们的假设 ARID1A -信号通路控制肿瘤干扰素γ反应性 在……里面 肿瘤微环境。 目标2是测试我们的假设 ARID1A -信号通路与效应器T细胞肿瘤相关 贩运、肿瘤免疫和治疗

Tumors characterized by limited Th1-type chemokine (e.g.CXCL9 and CXCL10) expression and low frequency of effector tumor infiltrating lymphocytes (TIL) in the microenvironment, render immune-cell-targeted regimens less likely to succeed. In patients with high grade serous ovarian cancer, a polycomb repressive complex 2 (PRC2) protein, enhancer of zeste 2 (EZH2)-based histone H3 lysine 27 trimethylation (H3K27me3) mediates a repression on CXCL9 and CXCL10 expression. It controls effector T cell tumor trafficking and impacts therapeutic efficacy of cancer immune therapy. Thus, epigenetic mechanism (e.g. PRC2) may control the “hot” vs “cold” phenotype of cancer and shape immunotherapeutic efficacy. In addition to PRC2, mammalian chromatin remodeler switch/sucrose non-fermentable (SWI/SNF) complexes (also called BAF complex for Brg-/Brama-associated factor complex) are important epigenetic machinery. AT - rich interactive domain-containing protein 1A (ARID1A) is a member of the SWI/SNF complex. Potential immunological role, immune regulatory mechanisms, immune-associated clinical significance, and therapeutic relevance of ARID1A are unknown in human cancer including human ovarian cancer. Our preliminary data show a deficiency in the IFNγ-signaling pathway in several ARID1A mutated ovarian clear carcinoma cells and ARID1A is required for intact CXCL9 and CXCL10 expression. Our previous work reveals that PRC2 complex represses CXCL9 and CXCL10 expression in high grade ovarian cancer. Thus, we hypothesize that there may be a dynamic balance between PRC2 (e.g. EZH2) and SWI/SNF (e.g. ARID1A) complexes in the control of IFNγ-responsiveness in ovarian cancer. To test this hypothesis, our project is to conduct comprehensive molecular, functional, translational, and clinical research on the nature of effector T cell tumor trafficking and IFNγ-pathway in the human ovarian carcinoma microenvironment, and will provide rich opportunities to take our understanding of effector T cell biology in the tumor to a new level of basic and practical application. The application is highly translational. Our specific aims are: Aim 1 is to test our hypothesis that ARID1A -signaling circuit controls tumor IFNγ-responsiveness in the tumor microenvironment. Aim 2 is to test our hypothesis that ARID1A -signaling circuit associates with effector T cell tumor trafficking, tumor immunity, and therapy