Apoptosis, Signaling Defects and T Lymphocyte Homeostasis in Patients with Cancer

癌症患者的细胞凋亡、信号传导缺陷和 T 淋巴细胞稳态

• 批准号: 7903454
• 负责人: Theresa L. Whiteside
• 金额: $ 24.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7903454
• 关键词: Address; Age; Apoptosis; Apoptotic; Binding; Biological Assay; Biological Markers; Blood Circulation; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cell Line; Cell surface; Cells; Clinical Trials; Color; DNA biosynthesis; Data; Defect; Development; Disease; Effector Cell; Evaluation; Flow Cytometry; Functional disorder; Half-Life; Head and Neck Cancer; Homeostasis; Human; Immune; Immune response; In Vitro; Interleukin-12; Interleukin-15; Interleukin-2; Interleukin-7; Kinetics; Label; Laboratories; Length; Lymphocyte; MCL1 protein; Malignant Neoplasms; Measures; Mediating; Mitochondria; Molecular; Molecular Target; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Production; Prognostic Factor; Proteins; Relative (related person); Signal Transduction; Site; Specificity; Surface Antigens; T-Cell Receptor; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Clinical Trial; Time; Tumor Antigens; Tumor Burden; Vesicle; Viral; Water; annexin A5; base; cohort; cytokine; design; drinking water; head and neck cancer patient; immune function; in vivo; lymph nodes; melanoma; novel; protective effect; response; restoration; telomere; therapy design; therapy development; tumor; volunteer

This project explores the fate of CD8+ effector T cells in patients with cancer. Our data show that tumor-infiltrating as well as circulating lymphocytes are susceptible to spontaneous apoptosis in these patients. CD8+ T cells which are particularly susceptible, bind Annexin V and/or have a low level of the T-cell receptor-associated zeta chain. Decreased T-cell numbers and dysfunction of T cells are common findings in patients with head and neck cancer (HNC) and melanoma. We will test the hypothesis that in patients with these cancers, tumor-specific CD8+ T cells are preferentially targeted for apoptosis, which disrupts normal lymphocyte homeostasis and leads to dysregulated anti-tumor responses. In Aim 1, a clinical trial will be performed to in vivo measure absolute production rates of CD4+ and CD8+ cells, their half-life and survival time in the circulation of patients with HNC, using deuterated drinking water to label DMA in these lymphocytes. In addition, TREC and telomere length assays will be performed in a larger cohort of HNC patients to corroborate a rapid T-cell turnover. In Aim 2, we will explore the preferential demise of CD8+ effector T cells by a combined use of T-cell surface and apoptosis biomarkers in multi-color flow cytometry. Various T-cell subsets, including tetramer+ tumor-specific T cells in the peripheral circulation of patients with HNC or melanoma will be targeted. Aim 3 will evaluate mechanisms responsible for CD8+ T-cell demise by focusing on the selected molecular targets in the Fas/FasL or mitochondria! pathways of apoptosis. Elimination of CD8+ T cells via a novel mechanism involving circulating membraneous vesicles (MV) will be studied. In Aim 4, effects of the cytokines known to regulate T-cell homeostasis (IL-2, IL-7, IL-12 and IL-15) on the molecular targets engaged in apoptosis will be evaluated as will mechanisms responsible for the protective effects on T cells of the anti-apoptotic protein Mcl-1. In all Aims, efforts will be made to relate expression and function of immune biomarkers studied in CD8+ T cells with the presence and activity of the disease and with the known prognostic factors for the disease. These studies will serve as a basis for the development of novel therapies designed to deliver survival factors to patients with cancer in order to rescue tumor-specific T cells from apoptosis, normalize homeostasis and amplify anti-tumor immune responses.

这个项目探索CD8+效应T细胞在癌症患者中的命运。我们的数据显示，肿瘤的浸润性 在这些患者中，循环中的淋巴细胞也容易发生自发性凋亡。 CD8+T细胞特别敏感，与Annexin V结合和/或T细胞水平较低 受体相关的Zeta链。T细胞数量减少和T细胞功能障碍是该病的常见表现 头颈部癌(HNC)和黑色素瘤患者。我们将检验这一假设，即在患有 这些癌症，肿瘤特异性CD8+T细胞优先被作为凋亡的目标，这破坏了正常的 淋巴细胞动态平衡，导致抗肿瘤反应失调。在目标1中，将进行临床试验 在体内测量CD4+和CD8+细胞的绝对生成率、半衰期和存活率 HNC患者的循环时间，使用氚饮用水标记这些中的DMA 淋巴细胞。此外，TREC和端粒长度分析将在更大的HNC队列中进行 患者证实了T细胞的快速更新。在目标2中，我们将探索CD8+的优先死亡 在多色流式细胞术中联合使用T细胞表面和凋亡生物标志物的效应T细胞。 各种T细胞亚群，包括四聚体+肿瘤特异性T细胞在慢性阻塞性肺疾病患者外周血中的表达 HNC或黑色素瘤将成为目标。AIM 3将通过以下方式评估CD8+T细胞死亡的机制 聚焦于Fas/FasL或线粒体中选定的分子靶点！细胞凋亡的途径。 通过一种涉及循环膜泡(MV)的新机制消除CD8+T细胞 学习。在目标4中，已知的调节T细胞稳态的细胞因子(IL-2、IL-7、IL-12和IL-15)的作用 关于参与细胞凋亡的分子靶点将被评估为负责 抗凋亡蛋白Mcl-1对T细胞的保护作用在所有目标中，将努力联系 免疫生物标记物在CD8+T细胞中的表达和功能 与疾病和已知的疾病预后因素有关。这些研究将作为 开发旨在为癌症患者提供生存因素的新疗法，以挽救 肿瘤特异性T细胞的凋亡，正常化动态平衡和放大抗肿瘤免疫反应。