Ovarian Cancer Epigenetics, Immunity and Therapy

卵巢癌表观遗传学、免疫和治疗

基本信息

批准号：
10408767
负责人：
WEIPING ZOU
金额：
$ 59.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10408767
关键词：
ARID Domain ARID1A gene ATP Hydrolysis ATP phosphohydrolase Affect 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

项目摘要

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Th1型趋化因子（例如CXCL9和CXCL10）和低频为特征的肿瘤微环境中效应肿瘤浸润淋巴细胞（TIL）成功的可能性较小。在高级浆液卵巢癌的患者中，Polycomb反射复合物2 （PRC2）蛋白质，Zeste 2（EZH2）的组蛋白H3赖氨酸27三甲基化（H3K27ME3）培养基的蛋白质 CXCL9和CXCL10表达式的表示。它控制效应T细胞肿瘤运输和影响癌症免疫治疗的治疗效率。这，表观遗传机制（例如PRC2）可能控制 “热”与癌症的“冷”表型和形状的免疫治疗效率。除PRC2外，哺乳动物染色质改建剂开关/蔗糖不可发酵（SWI/SNF）配合物（也称为BRG/BRAMA相关因子复合物的BAF复合物）是重要的表观遗传机制。在 - 富含交互结构域的蛋白质1a（ARID1A）是SWI/SNF复合物的成员。潜在的免疫学作用，免疫调节机制，免疫相关的临床意义和治疗相关性 Arid1a 在包括人卵巢癌在内的人类癌症中未知。我们的初步数据表明，在几个ARID1A突变的卵巢透明中，IFNγ信号途径缺乏完整的CXCL9和CXCL10表达需要癌细胞和ARID1A。我们以前的工作揭示了高级卵巢癌中的PRC2复合副本CXCL9和CXCL10表达。那，我们假设PRC2（例如EZH2）和SWI/SNF（例如ARID1A）之间可能存在动态平衡控制卵巢癌IFNγ反应性的复合物。为了检验这一假设，我们的项目是进行综合的分子，功能，转化和临床研究人类卵巢癌微环境中的细胞肿瘤运输和IFNγ-Pathway，并将提供丰富的机会将我们对肿瘤中效应的细胞生物学理解达到新的基本水平和实际应用。该应用程序是高度翻译的。我们的具体目的是：目的1是检验我们的假设 Arid1a - 信号电路控制肿瘤IFNγ反应性在肿瘤微环境。目标2是测试我们的假设 Arid1a - 信号电路与效应T细胞肿瘤的关联贩运，肿瘤免疫和治疗