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 这个项目的总体目标是确定雄激素受体拮抗和其他雄激素是如何 前列腺癌的剥夺疗法会影响人类的T细胞功能。雄激素缺乏是一块基石 在前列腺癌治疗中，通过剥夺雄激素受体信号来杀死肿瘤细胞， 关键增长信号。雄激素对多种生理系统具有多效性。在免疫系统中 它们通常被认为是免疫抑制，并被认为是造成性别差异的原因 观察男性和女性之间自身免疫力和癌症的比率。然而，雄激素剥夺的影响 前列腺癌患者对T细胞功能的影响尚不清楚。这与癌症治疗高度相关，因为 免疫疗法结合雄激素剥夺最近被证明能诱导持久的反应 一组正在接受雄激素剥夺治疗的转移性前列腺癌患者 独自一人。尽管如此，接受这种联合治疗的大多数患者仍然经历了癌症的进展。它是 了解雄激素剥夺影响T细胞功能的机制很重要 改善转移性前列腺癌以及雄激素驱动的其他癌症的联合治疗选择 受体信号转导(例如，雄激素受体阳性乳腺癌)。 这个项目的目的是：1)确定雄激素受体拮抗剂苯扎鲁胺对 人类T细胞体外功能，以及II)确定雄激素剥夺治疗对T细胞反应的影响 在前列腺癌患者身上。在目标1中，我们将检验这样一种假设，即拮抗T细胞内的雄激素受体 细胞促进T细胞增殖和1型细胞因子的分泌，减少建立和/或 维持T细胞的耗竭。这些研究将使用从外周血中分离出来的T细胞进行 一群健康的志愿者。T细胞将在体外用临床相关的雄激素受体拮抗剂进行治疗， 苯扎鲁胺。在目标2中，我们将检验前列腺癌患者雄激素缺乏改变的假说。 T细胞亚群的比例，改变了T细胞的转录图谱，并增加了 抗原特异性T细胞反应。在这些研究中，我们将从转移的患者的外周血中分离T细胞 前列腺癌患者在雄激素剥夺治疗开始前和治疗后6-12周收集。 这些配对样本将使我们能够清楚地确定雄激素剥夺疗法对T细胞的影响 癌症患者的表型和功能。这个项目将揭示雄激素如何 受体拮抗作用影响适应性免疫反应，从而潜在地改变抗肿瘤免疫。