Ovarian Cancer Epigenetics, Immunity and Therapy

卵巢癌表观遗传学、免疫和治疗

• 批准号: 10163133
• 负责人: WEIPING ZOU
• 金额: $ 62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163133
• 关键词: ARID Domain; ARID1A gene; ATP Hydrolysis; ATP phosphohydrolase; Affect; Biological; CXCL10 gene; CXCL9 gene; Cancer Patient; Cancer Vaccines; Cell physiology; Cells; Cellular biology; Chemotherapy-Oncologic Procedure; Chromatin; Chromatin Structure; Clinical; Clinical Research; Complex; Data; Enhancers; Epigenetic Process; Epithelial; Equilibrium; Frequencies; Genes; Genetic Transcription; Histologic; Histone H3; Human; Immune; Immune response; Immune signaling; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Interferon Type II; Interferons; Investigation; Knowledge; Ligands; Link; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methods; Molecular; Monoclonal Antibodies; Mutate; Mutation; Nature; Nucleosomes; Oncogenic; Outcome; Ovarian Carcinoma; Ovarian Clear Cell Tumor; Ovarian Endometrioid Adenocarcinoma; Ovarian Serous Adenocarcinoma; PD-1 pathway; Pathway interactions; Patients; Pattern; Phenotype; Polycomb; Proteins; Publishing; Regimen; Repression; Role; Serous; Shapes; Signal Pathway; Signal Transduction; Sucrose; T-Lymphocyte; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Work; adaptive immunity; base; cancer cell; cancer immunotherapy; cancer therapy; checkpoint therapy; chemokine; chemotherapy; chromatin remodeling; clinical predictors; clinically significant; effector T cell; empowered; experience; helicase; immunogenic; immunogenicity; improved; interest; member; neoplastic cell; novel; practical application; programmed cell death ligand 1; protein expression; receptor; response; stem; success; treatment response; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

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

以有限的Th 1型趋化因子（例如CXCL 9和CXCL 10）表达和低频率为特征的肿瘤 效应肿瘤浸润淋巴细胞（TIL）在微环境中，使免疫细胞靶向治疗方案 不太可能成功。在高级别浆液性卵巢癌患者中，多梳抑制复合物2 （PRC 2）蛋白，基于zeste 2（EZH 2）的增强子H3赖氨酸27三甲基化（H3 K27 me 3）介导 对CXCL 9和CXCL 10表达的抑制。它控制效应T细胞肿瘤的运输和影响 癌症免疫治疗的疗效。因此，表观遗传机制（例如PRC 2）可能控制了细胞的增殖。 “热”与“冷”癌症表型和形状免疫功效。 除了PRC 2，哺乳动物染色质重塑开关/蔗糖非发酵（SWI/SNF）复合物 (also称为BAF复合物的Brg-/Brama-相关因子复合物）是重要的表观遗传机制。在 - 富含相互作用结构域的蛋白1A（ARID 1A）是SWI/SNF复合物的成员。潜在 免疫学作用、免疫调节机制、免疫相关临床意义，以及 治疗相关性 ARID1A 在人类癌症包括人类卵巢癌中是未知的。 我们 初步数据显示，在几个ARID 1A突变的卵巢透明细胞中，IFNγ信号通路缺乏。 癌细胞和ARID 1A是完整的CXCL 9和CXCL 10表达所需的。我们之前的工作揭示了 PRC 2复合物抑制高级别卵巢癌中CXCL 9和CXCL 10的表达。因此我们 假设PRC 2（例如EZH 2）和SWI/SNF（例如ARID 1A）之间可能存在动态平衡 复合物在控制卵巢癌IFNγ-反应性中的作用。为了验证这一假设，我们的项目是 对效应T的性质进行全面的分子、功能、翻译和临床研究， 人卵巢癌微环境中的细胞肿瘤运输和IFNγ-通路，并将提供 丰富的机会，使我们对肿瘤中效应T细胞生物学的理解达到一个新的水平， 实际应用该应用程序是高度翻译。我们的具体目标是： 目的1是检验我们的假设， ARID1A - 信号通路控制肿瘤IFNγ-反应性 在 肿瘤微环境。 目标2是检验我们的假设， ARID1A - 信号通路与效应T细胞肿瘤相关 贩运、肿瘤免疫和治疗