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: 7481055
• 负责人: Theresa L. Whiteside
• 金额: $ 25.55万
• 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/7481055
• 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; Immune response; In Vitro; Interleukin-12; Interleukin-15; Interleukin-7; Kinetics; Label; Laboratories; Length; Lymphocyte; MCL1 protein; Malignant Neoplasms; Measures; Mediating; Mitochondria; Molecular; Molecular Target; Numbers; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Production; Prognostic Factor; Proteins; Rate; 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 Clinical Trial; Time; Tumor Antigens; Tumor Burden; Tumor Cell Line; Vesicle; Viral; Water; annexin A5; base; cohort; cytokine; design; drinking water; head and neck cancer patient; human MCL1 protein; 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.

该项目探讨了癌症患者中CD 8+效应T细胞的命运。我们的数据显示，肿瘤浸润 以及循环淋巴细胞对这些患者中的自发性细胞凋亡敏感。 特别易感的CD 8 + T细胞结合膜联蛋白V和/或具有低水平的T细胞免疫应答。 受体相关ζ链。T细胞数量减少和T细胞功能障碍是常见的结果， 头颈癌（HNC）和黑色素瘤患者。我们将检验一个假设，即在患有 在这些癌症中，肿瘤特异性CD 8 + T细胞优先靶向凋亡，这破坏了正常的细胞凋亡。 淋巴细胞稳态，并导致失调的抗肿瘤反应。在目标1中，将进行临床试验， 在体内测量CD 4+和CD 8+细胞的绝对产生率、它们的半衰期和存活率 在HNC患者的循环中的时间，使用氘代饮用水标记DMA在这些 淋巴细胞此外，将在更大的HNC队列中进行TREC和端粒长度测定， 病人来证实T细胞的快速更替在目标2中，我们将探索CD 8+的优先死亡 通过在多色流式细胞术中组合使用T细胞表面和凋亡生物标志物来检测效应T细胞。 各种T细胞亚群，包括四聚体+肿瘤特异性T细胞，在患有癌症的患者的外周循环中， HNC或黑色素瘤将被靶向。目的3将通过以下方法评估负责CD 8 + 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！凋亡的途径。 通过一种涉及循环膜囊泡（MV）的新机制消除CD 8 + T细胞， 研究了在目的4中，已知调节T细胞稳态的细胞因子（IL-2、IL-7、IL-12和IL-15）的作用 对参与细胞凋亡的分子靶点的影响将被评估， 抗凋亡蛋白Mcl-1对T细胞的保护作用。在所有目标中，将努力将 在CD 8 + T细胞中研究的免疫生物标志物的表达和功能， 疾病和疾病的已知预后因素。这些研究将作为 开发旨在向癌症患者提供生存因子的新疗法，以挽救 肿瘤特异性T细胞凋亡，正常化稳态和放大抗肿瘤免疫应答。