Exhaustion mechanisms in Merkel cell polyomavirus-specific T cells

默克尔细胞多瘤病毒特异性 T 细胞的耗竭机制

基本信息

批准号：
10647703
负责人：
Thomas Pulliam
金额：
$ 3.46万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10647703
关键词：
Activities of Daily Living Adoptive Cell Transfers Antigen-Presenting Cells Antigens Automobile Driving Biological Response Modifiers Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cessation of life Characteristics Clinical Clinical Trials Cytotoxic T-Lymphocytes Data Disease Exclusion Exhibits Failure Flow Cytometry Functional disorder Future Human Immune Immune response Immune system Immunotherapy Incidence Induced Mutation Inflammatory MHC Class I Genes Malignant Epithelial Cell Malignant Neoplasms Medical Education Merkel Cells Merkel cell carcinoma Mutation Nature Newly Diagnosed Oncoproteins Pathway interactions Patients Peripheral Pharmaceutical Preparations Phenotype Physicians Polyomavirus Polyomavirus Transforming Antigens Positioning Attribute Property Proteins RNA Reagent Research Role Sampling Scientist Signal Transduction Skin Cancer System T cell receptor repertoire sequencing T cell response T-Lymphocyte Techniques Training Tumor Antigens Tumor Escape UV induced Universities Viral Viral Proteins Viral Tumor Antigens Virus Washington Work career chronic infection cytokine cytotoxic cytotoxicity disorder control doctoral student exhaust exhaustion experimental study high dimensionality immunogenic melanoma mortality novel therapeutic intervention predicting response repository resistance mechanism responders and non-responders single-cell RNA sequencing tool transcriptome sequencing tumor tumor microenvironment

项目摘要

Abstract: Exhaustion mechanisms in Merkel cell polyomavirus-specific T cells Merkel cell carcinoma (MCC) is a rare and deadly cancer that is rapidly rising in incidence. Approximately 80% of MCC cases are caused by the Merkel cell polyomavirus (MCPyV) with the remaining 20% of cases caused by UV mutations. Immunotherapies targeting the PD-1 pathway have been highly successful in patients with MCC. Anti-PD-1 therapy works by reinvigorating T cells which have entered a dysfunctional state known as exhaustion. However, these therapies are still insufficient for long-term disease control in half of patients with advanced MCC and must be further studied. In most other cancers T cells recognize unique tumor mutations that vary from patient to patient. Because T cell targets are unique for each patient, studies of cancer-specific T cells are largely infeasible in mutationally driven cancers. However, in the case of virus- positive MCC, T cells recognize viral proteins driving the cancer which are shared across patients. Over the past decade our lab has developed tools to study T cells that recognize these viral oncoproteins. These tools put us in a unique position to study cancer-specific T cells from our extensive repository of more than 1,500 MCC patients. These reagents will be key to understanding why some patients do or do not respond to anti- PD-1 therapy in MCC as well as in other cancers where studies of tumor-specific cells would be infeasible. Aim 1 of this proposal will use newly developed techniques to extensively characterize circulating cancer- specific T cells in MCC patients over the course of anti-PD-1 therapy. Specifically, high dimensional flow cytometry, single cell RNA sequencing and T cell receptor sequencing will be used to characterize clonal, MCPyV-specific T cells over the course of anti-PD-1 therapy. T cells from patients that respond or do not respond to therapy will be compared to identify deficiencies in the T cell response which could be augmented in future clinical trials. Aim 2 will study a putative state of dysfunction that we identified in MCC-specific CD4 helper T cells. CD4 T cells are highly understudied but are known to be important for control of chronic infections and cancers. This aim will investigate the cytokine secretion profile and cytotoxic capacities of these cells to determine if they exert an immune suppressive phenotype. We hypothesize this dysfunction could be helping cancers evade the immune response and believe these studies could inform future clinical trials. This project is ideal for training young physician scientists due the highly translational nature of the research, the extensive background of Dr. Paul Nghiem in training previous MD-PhD students, and the quality research and medical education at the University of Washington. The activities detailed in this proposal will provide a strong background for a future career as a physician scientist.

摘要：默克尔细胞多瘤病毒特异性 T 细胞的耗竭机制默克尔细胞癌（MCC）是一种罕见且致命的癌症，发病率正在迅速上升。大约 80% 的 MCC 病例由默克尔细胞多瘤病毒 (MCPyV) 引起，其余 20% 的病例由紫外线突变引起。针对 PD-1 通路的免疫疗法在 MCC 患者。抗 PD-1 疗法的作用是重振已进入功能障碍状态的 T 细胞称为疲惫。然而，这些疗法仍然不足以长期控制一半的疾病晚期 MCC 患者，必须进一步研究。在大多数其他癌症中，T 细胞识别独特的肿瘤突变因患者而异。由于每个患者的 T 细胞靶标都是独特的，因此研究癌症特异性 T 细胞在突变驱动的癌症中基本上不可行。然而，就病毒而言—— MCC 呈阳性时，T 细胞识别驱动癌症的病毒蛋白，这些蛋白在患者之间共有。超过在过去的十年里，我们的实验室开发了一些工具来研究识别这些病毒癌蛋白的 T 细胞。这些工具使我们处于独特的地位，可以从我们超过 1,500 个的广泛存储库中研究癌症特异性 T 细胞 MCC 患者。这些试剂将是理解为什么一些患者对抗药物有反应或没有反应的关键。 PD-1 治疗 MCC 以及其他癌症，在这些癌症中，对肿瘤特异性细胞的研究是不可行的。该提案的目标 1 将使用新开发的技术来广泛表征循环癌症 - MCC 患者在抗 PD-1 治疗过程中的特异性 T 细胞。具体来说，高维流细胞计数、单细胞 RNA 测序和 T 细胞受体测序将用于表征克隆、抗 PD-1 治疗过程中的 MCPyV 特异性 T 细胞。来自有反应或无反应的患者的 T 细胞将比较对治疗的反应，以确定可增强的 T 细胞反应缺陷在未来的临床试验中。目标 2 将研究我们在 MCC 特异性 CD4 中发现的假定功能障碍状态辅助性T细胞。 CD4 T 细胞的研究还很不足，但已知它对于控制慢性疾病很重要感染和癌症。该目标将研究这些细胞因子的细胞因子分泌谱和细胞毒能力细胞以确定它们是否发挥免疫抑制表型。我们假设这种功能障碍可能是帮助癌症逃避免疫反应，并相信这些研究可以为未来的临床试验提供信息。由于该项目的高度转化性质，该项目是培训年轻医师科学家的理想选择研究、Paul Nghiem 博士在培养往届医学博士-博士生方面的广泛背景以及质量华盛顿大学的研究和医学教育。本提案中详述的活动将为未来作为医师科学家的职业生涯提供坚实的背景。