Single-cell dissection of CD4 T cell changes in patients with immune-related adverse events following PD-1 inhibition

PD-1 抑制后出现免疫相关不良事件的患者 CD4 T 细胞变化的单细胞解剖

基本信息

批准号：
10571532
负责人：
Sokratis Apostolidis
金额：
$ 17.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571532
关键词：
Affect Antigens Autoimmune Autoimmune Diseases Autoimmunity Bioinformatics Blood CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caring Cells Clinical Clinical Research Clonal Expansion Clonality Collaborations Communication Data Development Development Plans Dissection Early Diagnosis Early Intervention Early treatment Epigenetic Process Evaluation Event Exhibits Faculty Feedback Foundations Functional disorder Funding Gene Expression Profile Genetic Transcription Goals Grant Growth Helper-Inducer T-Lymphocyte Homeostasis Human Immune Immunization Immunotherapy Impairment Inflammatory Influenza vaccination Intervention Malignant Neoplasms Mediating Medical Memory Mentors Molecular Target Oncology Group PD-1 pathway Pathology Pathway interactions Patients Pennsylvania Phase Physicians Population Positioning Attribute Preparation Prevention Productivity Proxy Research Research Personnel Resolution Rheumatism Rheumatology Sampling Scientist Shapes Signal Transduction Surface T cell response T-Lymphocyte Testing Time Toxic effect Training Transcriptional Regulation Translational Research United States National Institutes of Health Universities Vaccination Vaccines Writing analytical tool anti-PD-1 anti-PD1 therapy autoimmune toxicity autoreactivity cancer immunotherapeutics cancer therapy career career development cellular targeting checkpoint inhibition cohort collaborative environment design epigenetic regulation experience fitness immune-related adverse events immunopathology influenza virus vaccine multimodality novel novel strategies permissiveness pre-clinical prevent programmed cell death protein 1 programs prospective recruit response seasonal influenza single cell analysis single cell technology skills systemic autoimmune disease tenure track tumor

项目摘要

Project Summary This application proposes a five-year research and training plan with a scientific focus on the mechanisms through which PD-1 checkpoint inhibition leads to immune-related adverse events (irAEs). The hypothesis is that de novo loss of PD-1 signaling enhances the antigen sensitivity of CD4 T cells and leads to the activation of autoreactive CD4 T cells that mediate irAE development. To investigate this hypothesis, the candidate will analyze two complementary human cohorts of his mentors: a) a prospective irAE cohort of patients on PD-1 immunotherapy to compare the early changes of CD4 T cells in patients who do (irAE+) and do not (irAE-) develop irAEs, and b) a cohort of patients on PD-1 immunotherapy that receive seasonal influenza vaccination to test whether any underlying immunopathology in irAE+ patients, not otherwise observed with evaluation of basal states, can be revealed with the help of immunization. Using the prospective irAE cohort, Aim 1 will evaluate whether patients that develop irAEs have a different naïve CD4 T cell epigenetic and transcriptional profile at baseline that allows robust activation of autoreactive CD4 T cells following PD-1 inhibition. Further, this aim will analyze the transcriptional profile and clonal diversity of the activated CD4 T cells generated after PD-1 inhibition in irAE+ patients. Using the aPD-1 cohort of influenza vaccination, Aim 2 will answer the question of whether PD-1 signaling is required to finetune the TCR threshold and transcriptional profile of CD4 T cell responses to maintain immune fitness and homeostasis. These studies will define the path through which PD-1 inhibition leads to the activation and propagation of autoreactive CD4 T cells to cause immune-mediated pathology. They will also identify cellular and molecular targets that can be used for early diagnosis and treatment of patients with rheumatologic and other irAEs. Scientifically, the candidate’s career development goals are to gain expertise in the conduct of clinical and translational research, bioinformatic analyses, single-cell technologies, and transcriptional and epigenetic regulation of autoimmune pathways in patient samples. Professionally, the candidate aims to gain experience in scientific writing, grant preparation, communication, and data presentation culminating to an R01 submission. To facilitate the candidate’s growth as a physician-scientist, this proposal combines novel experimental single-cell approaches and a specific career development plan designed by the candidate and his mentors, Dr. Wherry and Dr. Laufer. The candidate’s long-term goal is to transition to a tenure- track faculty position and to develop an independent NIH-funded research program focusing on the mechanisms of autoimmunity and T cell dysfunction to ultimately prevent and treat rheumatologic diseases. The rich scientific and collaborative environment at the University of Pennsylvania will position the candidate to have a highly impactful, translational research career in human autoimmunity.

项目摘要该申请提出了一项为期五年的研究和培训计划，并科学地关注了机制 PD-1检查点抑制导致免疫相关的不良事件（IRAE）。该假设是从头丧失PD-1信号传导增强了CD4 T细胞的抗原敏感性，并导致激活介导IRAE发育的自动反应性CD4 T细胞。为了调查这一假设，候选人将分析他的导师的两个完整人群：a）PD-1患者的前瞻性IRAE队列免疫疗法比较（IRAE+）患者中CD4 T细胞的早期变化，并且不发展（IRAE-） IRAE和B）在PD-1免疫疗法上接受季节性流感疫苗接种以测试的患者队列 IRAE+患者中是否有任何潜在的免疫病理学，否则未通过评估基本观察到国家可以在免疫帮助的帮助下揭示。使用潜在的IRAE队列，AIM 1将评估在基线允许在PD-1抑制后强大地激活自动反应性CD4 T细胞。此外，这个目标将分析PD-1抑制后激活的CD4 T细胞的转录曲线和克隆多样性在IRAE+患者中。使用APD-1疫苗接种的APD-1队列，AIM 2将回答是否是否需要PD-1信号传导才能鉴定CD4 T细胞反应的TCR阈值和转录曲线保持免疫健康和稳态。这些研究将定义PD-1抑制引导的路径自动反应性CD4 T细胞的激活和传播引起免疫介导的病理。他们会的还确定可用于早期诊断和治疗患者的细胞和分子靶标风湿病和其他伊拉斯。从科学上讲，候选人的职业发展目标是获得专业知识在临床和翻译研究的进行中，生物信息学分析，单细胞技术和患者样品自身免疫途径的转录和表观遗传调节。专业，候选人旨在获得科学写作，赠款准备，沟通和数据展示的经验最终提交R01。为了促进候选人作为身体科学家的成长，该提议结合了新颖的实验单细胞方法和特定的职业发展计划候选人及其导师沃尔博士和劳弗博士。候选人的长期目标是过渡到任期 - 跟踪教师职位并制定一项独立的NIH资助研究计划，重点是机制自身免疫性和T细胞功能障碍最终预防和治疗风湿病。富裕的科学宾夕法尼亚大学的协作环境将使候选人定位人类自身免疫性的有影响力的翻译研究职业。