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

• 批准号: 10064717
• 负责人: Thomas Pulliam
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10064717
• 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; Diagnosis; 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 Neoplasms; Medical Education; Merkel Cells; Merkel cell carcinoma; Mutation; Nature; 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 response; T-Cell Receptor; T-Lymphocyte; Techniques; Time; Training; Tumor Antigens; Tumor Escape; UV induced; Universities; Viral; Viral Proteins; Viral Tumor Antigens; Virus; Washington; Work; base; career; chronic infection; cytokine; cytotoxic; cytotoxicity; disorder control; doctoral student; exhaust; exhaustion; experimental study; high dimensionality; immunogenic; melanoma; mortality; novel therapeutic intervention; predicting response; programs; repository; resistance mechanism; responders and non-responders; single-cell RNA sequencing; tool; transcriptome sequencing; tumor; tumor microenvironment

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细胞中的耗尽机制 默克尔细胞癌（MCC）是一种罕见且致命的癌症，发病率迅速增加。大约 80％的MCC病例是由Merkel细胞多瘤病毒（MCPYV）引起的，其余20％ 由紫外线突变引起。针对PD-1途径的免疫疗法在 MCC患者。抗PD-1疗法通过重新活化进入功能失调状态的T细胞来起作用 被称为疲惫。但是，这些疗法仍然不足以控制一半的长期疾病 患有晚期MCC的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。因为T细胞靶标对于每个患者都是独一无二的，所以 在突变驱动的癌症中，癌症特异性T细胞在很大程度上是不可行的。但是，在病毒的情况下 阳性MCC，T细胞识别驱动癌症的病毒蛋白，这些蛋白在患者中共享。在 过去的十年，我们的实验室开发了研究这些病毒癌蛋白的T细胞的工具。这些工具 使我们处于独特的位置，可以从我们的1,500多个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某些患者对抗抗反应反应或不反应的关键 MCC以及其他肿瘤特异性细胞研究的PD-1治疗是不可行的。 该提案的目标1将使用新开发的技术来广泛表征循环癌的表征 在抗PD-1治疗过程中，MCC患者的特定T细胞。具体而言，高维流量 细胞仪，单细胞RNA测序和T细胞受体测序将用于表征克隆， 在抗PD-1治疗过程中，MCPYV特异性T细胞。来自反应或反应的患者的T细胞 将比较对治疗的反应，以确定可以增加T细胞反应中的缺陷 在以后的临床试验中。 AIM 2将研究我们在MCC特异性CD4中确定的推定功能障碍状态 助手T细胞。 CD4 T细胞被高度研究，但已知对于控制慢性很重要 感染和癌症。该目标将研究这些目标的细胞因子分泌谱和细胞毒性能力 细胞确定它们是否施加免疫抑制表型。我们假设这种功能障碍可能是 帮助癌症逃避免疫反应，并认为这些研究可以为未来的临床试验提供信息。 该项目是培训年轻医师科学家的理想选择 研究，保罗·恩吉姆（Paul Nghiem）博士在培训以前的MD-PHD学生中的广泛背景以及质量 华盛顿大学的研究和医学教育。本提案中详细介绍的活动将 为医生科学家提供未来职业的强大背景。