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：
10445347
负责人：
Amy E Moran
金额：
$ 54.46万
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/10445347
关键词：
2019-nCoV 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 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 Sciences Hormones Human Immunity Immunosuppression Immunotherapy In complete remission Interferons Leukocytes Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Oregon Outcome PD-1 blockade PD-L1 blockade Patients Pharmacology Precipitation Predisposition Prostate Sarcoma Receptor Inhibition Receptor Signaling Regulator Genes Repression Resistance Risk Role Sampling Shapes T cell differentiation T cell response T-Lymphocyte Testing Testosterone Time Transcriptional Regulation Tumor Antigens Tumor Immunity United States Universities Viral Virus Woman XCL1 gene 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 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 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.

项目概要众所周知，雄激素具有免疫抑制作用，但癌症免疫疗法的使用却没有考虑到当地雄激素浓度或患者的性别。我们提供的证据表明，针对雄激素受体对于前列腺癌小鼠模型中有效的 T 细胞特异性免疫治疗是必需的肉瘤和转移性前列腺癌的人体临床试验。在患者活检中，我们观察到一个惊人的现象 CD8 T 细胞中低雄激素受体活性与 PD-1 靶向反应之间的相关性免疫疗法。我们在去势抵抗性前列腺癌的新型小鼠模型中验证了我们的观察结果并证明需要抑制雄激素受体才能实现有效的 PD-L1 免疫治疗。此外，肿瘤消退需要 CD8 T 细胞，这表明 T 细胞内在的 AR 活性可以调节反应到免疫治疗。扩展这些研究，我们分离出活化的 CD8 T 细胞并观察到强烈的关联雄激素受体与染色质修饰剂的结合。计算机实验揭示了典型的雄激素 Ifng 和 Gzmb 位点的开放染色质区域中的响应元件。我们观察到雄激素的结合这些区域内的受体，重要的是，能够抑制与小分子抑制剂的这种相互作用。抑制这种相互作用会增加功能失调的 CD8 T 细胞的功能能力；进一步的功能状态通过 PD-L1 阻断而放大。综上所述，这些观察结果表明雄激素受体信号传导可以通过检查点封锁来强化 T 细胞功能失调的染色质状态，从而限制其恢复活力。至据我们所知，这是第一个建立雄激素受体直接作用的实验模型调节免疫治疗反应性的活性。该提案的目的是了解 CD8 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 CD8 T 中的雄激素受体活性细胞通过转录和表观遗传将功能重新激活限制为免疫检查点阻断效应基因的抑制。我们将在以下目标中检验这一假设。 1）评估是否有AR活性通过直接 DNA 结合抑制 T 细胞效应基因； 2) 确定 AR 信号是否强制实施抑制功能失调的 CD8 T 细胞的染色质状态； 3) 确定 T 细胞内在 AR 的丧失是否足以恢复对检查站封锁的响应能力。这些研究共同为理解激素介导的癌症抵抗力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前列腺癌患者的免疫疗法，并预计我们的观察结果将适用于此之外疾病以改善存在雄激素的癌症的免疫治疗结果。