Effects of androgen receptor antagonists on human T cell function

雄激素受体拮抗剂对人T细胞功能的影响

• 批准号: 10515248
• 负责人: Susan E Murray
• 金额: $ 40.42万
• 依托单位: UNIVERSITY OF PORTLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515248
• 关键词: Address; Adoptive Cell Transfers; Affect; American; Androgen Receptor; Androgens; Antiandrogen Therapy; Antigens; Autoimmune Diseases; Autoimmunity; Award; Blood Cells; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cell physiology; Cessation of life; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Disease Progression; Environment; Estrogens; Female; Funding; Gene Expression Profile; Goals; Gonadal Steroid Hormones; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Memory; Metastatic Prostate Cancer; Mus; Outcome; Output; PD-1 blockade; Patients; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Physiological; Play; Population; Predisposition; Prostate Cancer therapy; Receptor Signaling; Regulation; Reproductive system; Research; Role; Sampling; Sex Differences; Signal Transduction; System; T cell differentiation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Time; Tumor Immunity; Universities; Woman; adaptive immune response; androgen deprivation therapy; antagonist; anti-PD-1; antigen-specific T cells; arm; base; cancer care; cancer risk; cancer therapy; cell killing; cell type; clinical effect; clinically relevant; cytokine; deprivation; effector T cell; enzalutamide; exhaustion; expectation; healthy volunteer; improved; improved outcome; in vitro Model; in vitro testing; in vivo; insight; male; malignant breast neoplasm; men; neoplastic cell; patient subsets; peripheral blood; pleiotropism; programmed cell death protein 1; receptor expression; response; sexual dimorphism; standard care; standard of care; success; tumor; tumor progression; undergraduate research

SUMMARY/ABSTRACT The overall objective of this project is to determine how androgen receptor antagonism and other androgen deprivation therapies used in prostate cancer affect human T cell function. Androgen deprivation is a cornerstone of prostate cancer therapy, in which tumor cells are killed by depriving them of androgen receptor signaling, a key growth signal. Androgens have pleiotropic effects on numerous physiological systems. In the immune system, they are generally considered immune inhibitory and are thought to contribute to the sex differences observed between men and women in rates of autoimmunity and cancer. Yet the effect of androgen deprivation on T cell function in men with prostate cancer is not known. This is highly relevant to cancer treatment, because immunotherapy in combination with androgen deprivation was recently shown to induce a durable response in a subset of patients with metastatic prostate cancer who were progressing on androgen deprivation therapy alone. Nonetheless, the majority of patients receiving this combination still endured cancer progression. It is important to understand the mechanisms by which androgen deprivation affects T cell function in order to improve combination therapy options for metastatic prostate cancer, as well as other cancers driven by androgen receptor signaling (e.g., androgen receptor positive breast cancer). The aims of this project are to i) determine the effect of the androgen receptor antagonist, enzalutamide, on human T cell function in vitro, and ii) determine the effect of androgen-deprivation therapy on T cell responses in prostate cancer patients. In aim 1, we will test the hypothesis that antagonizing androgen receptors within T cells increases T cell proliferation and type 1 cytokine secretion and decreases establishment and/or maintenance of T cell exhaustion. These studies will be performed using T cells isolated from peripheral blood of healthy volunteers. T cells will be treated in vitro with the clinically relevant androgen receptor antagonist, enzalutamide. In aim 2, we will test the hypothesis that androgen deprivation in men with prostate cancer alters the proportions of T cell subsets, changes the transcriptional profile of T cells, and increases the magnitude of antigen-specific T cell responses. In these studies, we will isolate T cells from peripheral blood of metastatic prostate cancer patients collected both before and 6-12 weeks after initiation of androgen deprivation therapy. These paired samples will allow us to clearly establish the effect of androgen deprivation therapy on T cell phenotype and function in cancer patients. This project will reveal important information about how androgen receptor antagonism impacts the adaptive immune response, and thus potentially alters anti-tumor immunity.

摘要/摘要 该项目的总体目的是确定雄激素受体拮抗和其他雄激素如何 前列腺癌中使用的剥夺疗法会影响人类T细胞功能。雄激素剥夺是一个基石 前列腺癌疗法，其中肿瘤细胞通过剥夺雄激素受体信号传导而杀死 关键增长信号。雄激素对众多生理系统具有多效性。在免疫中 系统，它们通常被认为是免疫抑制性的，被认为会导致性别差异 在自身免疫和癌症率的男性和女性之间观察到。然而雄激素剥夺的影响 关于前列腺癌男性的T细胞功能尚不清楚。这与癌症治疗高度相关，因为 最近证明，免疫疗法与雄激素剥夺相结合，可引起持久的反应 在雄激素剥夺疗法上进展的转移性前列腺癌患者的一部分 独自的。但是，大多数接受这种组合的患者仍然忍受了癌症的进展。这是 了解雄激素缺乏影响T细胞功能的机制很重要 改善转移性前列腺癌的组合疗法选择，以及其他由雄激素驱动的癌症 受体信号传导（例如，雄激素受体阳性乳腺癌）。 该项目的目的是i）确定雄激素受体拮抗剂enzalutamide对 人体T细胞在体外和II）确定雄激素剥夺治疗对T细胞反应的影响 在前列腺癌患者中。在AIM 1中，我们将测试以下假设。 细胞增加T细胞增殖和1型细胞因子分泌，并减少建立和/或 维持T细胞耗尽。这些研究将使用从外周血分离的T细胞进行 健康的志愿者。 T细胞将在临床上相关的雄激素受体拮抗剂中在体外进行治疗， 恩扎拉胺。在AIM 2中，我们将检验以下假设：前列腺癌男性的雄激素剥夺会改变 T细胞子集的比例，改变T细胞的转录曲线，并增加 抗原特异性T细胞反应。在这些研究中，我们将将T细胞与转移性的外围血液分离 前列腺癌患者在开始雄激素剥夺疗法之前和6-12周收集。 这些配对样品将使我们能够清楚地确定雄激素剥夺治疗对T细胞的影响 癌症患者的表型和功能。该项目将揭示有关雄激素的重要信息 受体拮抗作用会影响适应性免疫反应，因此可能会改变抗肿瘤免疫力。