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

基本信息

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
项目类别：
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

项目摘要

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标是确定雄激素受体与其他雄激素的拮抗作用如何前列腺癌中使用的剥夺疗法会影响人类 T 细胞功能。雄激素剥夺是基石前列腺癌治疗中，通过剥夺肿瘤细胞的雄激素受体信号传导来杀死肿瘤细胞，这是一种关键增长信号。雄激素对许多生理系统具有多效性作用。在免疫方面系统中，它们通常被认为是免疫抑制性的，并且被认为是造成性别差异的原因观察男性和女性的自身免疫和癌症发生率。然而雄激素剥夺的影响对患有前列腺癌的男性 T 细胞功能的影响尚不清楚。这与癌症治疗高度相关，因为最近显示，免疫疗法与雄激素剥夺相结合可诱导持久的反应正在接受雄激素剥夺治疗的转移性前列腺癌患者的子集独自的。尽管如此，大多数接受这种组合的患者仍然经历了癌症进展。这是了解雄激素剥夺影响 T 细胞功能的机制非常重要，以便改善转移性前列腺癌以及其他由雄激素驱动的癌症的联合治疗选择受体信号传导（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恩杂鲁胺对体外人类 T 细胞功能，以及 ii) 确定雄激素剥夺疗法对 T 细胞反应的影响在前列腺癌患者中。在目标 1 中，我们将检验以下假设：拮抗 T 内的雄激素受体细胞增加 T 细胞增殖和 1 型细胞因子分泌，并减少建立和/或维持T细胞耗竭。这些研究将使用从外周血中分离的 T 细胞进行健康的志愿者。 T细胞将在体外用临床相关的雄激素受体拮抗剂进行处理，恩杂鲁胺。在目标 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 细胞亚群的比例，改变 T 细胞的转录谱，并增加抗原特异性 T 细胞反应。在这些研究中，我们将从转移性肿瘤的外周血中分离出 T 细胞。前列腺癌患者在雄激素剥夺治疗开始前和开始后6-12周收集数据。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。该项目将揭示有关雄激素如何作用的重要信息受体拮抗作用影响适应性免疫反应，从而可能改变抗肿瘤免疫。