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.

项目摘要众所周知，雄激素是免疫抑制作用的，但无需考虑使用癌症免疫疗法局部雄激素浓度或患者的性别。我们提供了针对雄激素的证据在前列腺癌小鼠模型和肉瘤和转移性前列腺癌的人类临床试验。在患者活检中，我们观察到了惊人的 CD8 T细胞中低雄激素受体活性与靶向PD-1的响应之间的相关性免疫疗法。我们在一种新型的castration抗性前列腺癌的小鼠模型中验证了我们的观察结果并证明对雄激素受体抑制需要有效的PD-L1免疫疗法。此外，肿瘤回归所需的CD8 T细胞表明T细胞固有的AR活性可以调节反应进行免疫疗法。扩展了这些研究，我们分离了激活的CD8 T细胞，并观察到了强的关联带有染色质修饰剂的雄激素受体。在计算机实验中进行的表现显示了规范的雄激素 IFNG和GZMB基因座的开放染色质区域中的响应元件。我们观察到雄激素的结合这些区域内的受体，重要的是，抑制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CD8 T细胞的功能能力。进一步的功能状态由PD-L1封锁扩增。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阻滞来强制T细胞的功能失调的T细胞染色质状态。到最好的知识这是第一个为雄激素受体建立直接作用的实验模型调节对免疫疗法的反应性的活动。该建议的目的是了解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限制功能性重新感染至免疫检查点阻滞抑制效应基因。我们将在以下目的中检验这一假设。 1）评估AR活动是否活性通过直接DNA结合抑制T细胞效应基因； 2）确定AR信号是否强制性抑制作用功能失调的CD8 T细胞中的染色质状态； 3）确定T细胞内在AR的丢失是否足以恢复对检查点封锁的响应能力。这些研究共同提供了一个理解激素介导的对癌症的抗性的框架免疫疗法。重要的是，我们将对雄激素如何限制有效的方式有批判性的理解前列腺癌患者的免疫疗法，预计我们的观察结果将适用疾病以改善存在雄激素的癌症的免疫疗法结局。