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Understanding how T cell intrinsic androgen receptor activity influences cell differentiation and dysfunction

了解 T 细胞内在雄激素受体活性如何影响细胞分化和功能障碍

基本信息

批准号：
10673078
负责人：
Amy E Moran
金额：
$ 53.37万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673078
关键词：
2019-nCoV ATAC-seq Activities of Daily Living Androgen Antagonists Androgen Receptor Androgen Response Element Androgens Autoimmune Diseases Binding Biological Assay Biopsy CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cancer Model Cancer Patient Castration Cell Differentiation process Cell Nucleus Cell physiology Cells Cessation of life Chromatin Chromatin Remodeling Factor Chronic Clinical Trials Combined Modality Therapy Complex DNA Binding DNA receptor Disease EZH2 gene Effectiveness Epigenetic Process Experimental Models Functional disorder Gene Expression Genes Genetic Genetic Transcription Genomics Goals Gonadal Steroid Hormones Grant Health Hormones Human Immunity Immunosuppression Immunotherapy In complete remission Leukocytes Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Oregon Outcome PD-1 blockade PD-L1 blockade Patients Precipitation Predisposition Prostate Sarcoma Receptor Inhibition Receptor Signaling Regulator Genes Repression Resistance Risk Role Sampling Science Shapes T cell differentiation T-Lymphocyte Testing Testosterone Time Transcriptional Regulation Tumor Antigens Tumor Immunity United States Universities Viral Virus Woman androgen deprivation therapy androgen sensitive antagonist anti-PD-L1 therapy anti-PD1 therapy antigen-specific T cells cancer immunotherapy castration resistant prostate cancer effector T cell enzalutamide exhaust exhaustion experimental study histone methyltransferase immune checkpoint blockade improved in silico inhibitor male men mortality mouse model novel novel therapeutic intervention pathogen pharmacologic programmed cell death ligand 1 programmed cell death protein 1 prostate cancer model receptor binding recruit response sex single-cell RNA sequencing small molecule inhibitor standard of care synergism treatment strategy tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Androgens are well known to be immunosuppressive, yet cancer immunotherapy is used without consideration of local androgen concentrations or the sex of the patient. We present evidence that targeting the androgen receptor is necessary for effective T cell-specific immunotherapy in mouse models of prostate cancer and sarcoma and in a human clinical trial of metastatic prostate cancer. In patient biopsies, we observed a striking correlation between low androgen receptor activity in CD8 T cells and response to PD-1 targeted immunotherapy. We validated our observations in a novel mouse model of castration resistant prostate cancer and demonstrated a requirement for androgen receptor inhibition to permit effective PD-L1 immunotherapy. Moreover, tumor regression required CD8 T cells suggesting T cell intrinsic AR activity could regulate response to immunotherapy. Extending these studies, we isolated activated CD8 T cells and observed a strong association of androgen receptor with chromatin modifiers. Performing in silico experiments revealed canonical androgen response elements in open chromatin regions of the Ifng and Gzmb loci. We observed binding of the androgen receptor within these regions and importantly, the ability to inhibit this interaction with a small molecule inhibitor. Inhibiting this interaction increased the functional capacity of dysfunctional CD8 T cells; a functional state further amplified by PD-L1 blockade. Taken together, these observations suggest that androgen receptor signaling could enforce the dysfunctional chromatin state of T cells limiting reinvigoration by checkpoint blockade. To the best of our knowledge this is the first experimental model to establish a direct role for androgen receptor activity on regulating responsiveness to immunotherapy. The goal of this proposal is to understand the mechanism(s) by which androgen receptor activity in CD8 T cells limits the effectiveness of cancer immunotherapy. We hypothesize that androgen receptor activity in CD8 T cells limits functional re-invigoration to immune checkpoint blockade by transcriptional and epigenetic repression of effector genes. We will test this hypothesis in the following Aims. 1) Evaluate whether AR activity represses T cell effector genes by direct DNA binding; 2) Determine whether AR signaling enforces a repressive chromatin state in dysfunctional CD8 T cells; and 3) Determine whether loss of T cell intrinsic AR is sufficient to restore responsiveness to checkpoint blockade. Together, these studies provide a framework for understanding hormone mediated resistance to cancer immunotherapy. Importantly, we will gain a critical understanding of how androgen could limit effective immunotherapy in prostate cancer patients and anticipate that our observations will be applicable beyond this disease to improve immunotherapy outcomes in cancers where androgens are present.

项目摘要雄激素是众所周知的免疫抑制，但癌症免疫治疗使用没有考虑局部雄激素浓度或患者的性别。我们提出的证据表明，受体对于前列腺癌小鼠模型中有效的T细胞特异性免疫疗法是必需的，肉瘤和转移性前列腺癌的人类临床试验。在患者活检中，我们观察到一个惊人的 CD 8 T细胞中的低雄激素受体活性与对PD-1靶向的应答之间的相关性免疫疗法。我们在一种新的去势抵抗性前列腺癌小鼠模型中验证了我们的观察结果并证明需要雄激素受体抑制以允许有效的PD-L1免疫治疗。此外，肿瘤消退需要CD 8 T细胞，表明T细胞内在AR活性可以调节应答到免疫疗法。扩展这些研究，我们分离了活化的CD 8 T细胞，并观察到与CD 8 T细胞的强相关性。雄激素受体与染色质修饰剂。计算机模拟实验显示，典型雄激素在Ifng和Gzmb基因座的开放染色质区域中的响应元件。我们观察到雄激素这些区域内的受体，重要的是，抑制这种与小分子抑制剂相互作用的能力。抑制这种相互作用增加了功能失调的CD 8 T细胞的功能能力;功能状态进一步通过PD-L1阻断扩增。总之，这些观察结果表明，雄激素受体信号转导可以通过检查点阻断来加强T细胞的功能失调的染色质状态，从而限制恢复活力。到据我们所知，这是第一个建立雄激素受体直接作用的实验模型。调节对免疫疗法的反应性的活性。本提案的目的是了解CD 8 T细胞中雄激素受体活性的机制。限制了癌症免疫疗法的有效性。我们假设CD 8 T细胞中的雄激素受体活性细胞通过转录和表观遗传将功能恢复限制于免疫检查点阻断抑制效应基因。我们将在以下目标中检验这一假设。1)评估AR活动是否通过直接DNA结合抑制T细胞效应基因; 2）确定AR信号传导是否强制抑制T细胞效应基因; 功能失调的CD 8 T细胞中的染色质状态;和3）确定T细胞内源性AR的丧失是否足以恢复对检查站封锁的反应能力。总之，这些研究为理解激素介导的癌症抗性提供了一个框架免疫疗法。重要的是，我们将对雄激素如何限制有效的前列腺癌患者的免疫治疗，并预计我们的观察将适用于此之外在存在雄激素的癌症中改善免疫治疗结果。