Unraveling the Role of PD-1 in CD8+ Tissue-Resident Memory T Cell Homeostasis and Epithelial Damage in Human Colitis

揭示 PD-1 在 CD8 组织驻留记忆 T 细胞稳态和人类结肠炎上皮损伤中的作用

基本信息

批准号：
10448872
负责人：
Molly Thomas
金额：
$ 17.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448872
关键词：
ATAC-seq Antibodies Apoptosis Area Autoimmunity Award B-Cell Antigen Receptor Biological Assay Blocking Antibodies Blood Blood Circulation CD8-Positive T-Lymphocytes CD8B1 gene CEACAM7 gene CTLA4 blockade CTLA4 gene CXCL11 gene CXCL13 gene CXCR3 gene Cells Chemotaxis Chromatin Clinical Colitis Colon Colonic inflammation Colonoscopy Complex Cytotoxic T-Lymphocytes Data Data Set Defect Development Diagnosis Disease Disseminated Malignant Neoplasm Down-Regulation Endothelial Cells Epigenetic Process Epithelial Epithelial Cells Gastroenterology Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Profile General Hospitals Genes Genetic Transcription Genomics Goals Health Heterogeneity Home Homeostasis Homing Human IL17 gene IL7R gene Immune Immune Tolerance Immune checkpoint inhibitor Immune system Immunity Immunofluorescence Microscopy Immunologic Receptors Immunologics Immunology Immunooncology Immunotherapy In Situ In Vitro Individual Inflammation Inflammatory Bowel Diseases Interferon Type II Interferons Interleukin-10 Interleukin-17 Ligands Malignant Neoplasms Maps Massachusetts Mediating Medicine Memory Mentors Mesenchymal Microscopy Modeling Mollies Monoclonal Antibodies Mucous Membrane Mus NR4A1 gene Oncology Organoids PD-1 blockade PD-1 inhibitors Pathologic Patients Phenotype Physicians Play Population Positioning Attribute Program Development Public Health Reporting Research Role Scientist Signal Transduction Solid Neoplasm System T cell receptor repertoire sequencing T memory cell T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TCR Activation Testing Therapeutic Tissues Toxic effect Up-Regulation Work anti-PD-1 base biobank cancer therapy career development checkpoint therapy cohort cytokine cytotoxic cytotoxicity diagnostic tool effector T cell epithelial injury exhaustion experimental study fighting gastrointestinal immune-related adverse events immunoregulation improved innovation instructor interleukin-22 medical schools peripheral blood prevent programmed cell death ligand 1 programmed cell death protein 1 programs prospective receptor response side effect single-cell RNA sequencing skills therapeutic target treatment strategy water channel

项目摘要

Project Summary Monoclonal antibodies against co-inhibitory immune receptors PD-1 and CTLA-4 [immune checkpoint inhibitors (ICIs)] have revolutionized immuno-oncology by reversing T cell exhaustion and harnessing the power of the immune system to fight solid tumors. Although ICI therapy has improved the survival of patients with metastatic cancer, treatments are unfortunately limited by the development of immune-related adverse events. Colitis is the most common, severe side effect of ICIs – seen in 5-10% of patients on PD-1 and up to 50% of patients on dual PD-1/CTLA-4 blockade – and is marked by epithelial injury and apoptosis. To date, little is understood about the immunologic underpinnings of PD-1 colitis, in part because mice treated with PD-1-blocking antibodies do not readily develop gastrointestinal toxicities. This proposal presents a five-year research career development program focused on understanding the immune drivers of human colitis that develops after PD-1 blockade [i.e., immunotherapy-related colitis (irColitis)]. Dr. Molly Thomas is an Instructor of Medicine at Harvard Medical School in the Division of Gastroenterology at Massachusetts General Hospital. This award will provide Dr. Thomas with the support necessary to test the hypothesis that irColitis is caused by the expansion of specific colon CD8+ T-resident memory (Trm) cells into cytotoxic effectors that produce IL-26 and IL-17A and home directly to damaged epithelium where they have deleterious effects on epithelial turnover and absorptive function. This hypothesis will be tested through the following aims: (Aim 1) Define the epigenetic landscapes and effector functions of distinct colonic CD8+ Trm and Trm-derived effectors; (Aim 2) Determine if CD8+ T effectors detected in the colon mucosa of irColitis patients circulate in blood and which blood immune cell states track with disease; (Aim 3) Map interactions between CD8+ Trms and damaged epithelial cells to understand how PD-1 inhibition leads to interferon-dependent defects in CD8+ Trm homing and epithelial absorptive function. Through these proposed aims, Dr. Thomas will map the complex interactions between CD8+ Trms and damaged colonic epithelium following PD-1 blockade. She will work under the guidance of her primary mentor Dr. Nir Hacohen, an expert in immuno-oncology and autoimmunity, and her co-mentor Dr. Alexandra-Chloé Villani, an expert in leveraging single cell genomics to understand immune heterogeneity in health and disease. The proposed experiments, analyses, and didactic work will provide Dr. Thomas with a unique set of skills that will enable her to transition to independence as a physician-scientist studying immune- mediated gastrointestinal diseases. These studies will define mechanisms by which IL-26+ and IL-17A+ CD8+ T cell effectors orchestrate pathologic inflammation and will allow for the development of diagnostic tools and treatment strategies that will be broadly applicable to irColitis patients and those with inflammatory bowel disease. By year four of this five-year award, Dr. Thomas will be well-positioned to develop an R01 application to define pathologic Trm responses in the human gastrointestinal tract and therapeutic targets to treat irColitis.

项目概要针对共抑制性免疫受体 PD-1 和 CTLA-4 的单克隆抗体 [免疫检查点抑制剂 (ICIs)] 通过逆转 T 细胞耗竭并利用 T 细胞的力量，彻底改变了免疫肿瘤学尽管 ICI 治疗提高了转移性患者的生存率。不幸的是，癌症的治疗受到免疫相关不良事件的限制。 ICI 最常见、最严重的副作用——5-10% 的 PD-1 患者和高达 50% 的 PD-1 患者出现这种副作用 PD-1/CTLA-4 双重阻断——以上皮损伤和细胞凋亡为标志，迄今为止，人们对此知之甚少。关于 PD-1 结肠炎的免疫学基础，部分原因是接受 PD-1 阻断治疗的小鼠抗体不易产生胃肠道毒性该提案提出了为期五年的研究生涯。开发计划的重点是了解 PD-1 之后发生的人类结肠炎的免疫驱动因素封锁 [即免疫治疗相关结肠炎 (irColitis)]。莫莉·托马斯 (Molly Thomas) 博士是该校的医学讲师。哈佛医学院马萨诸塞州总医院胃肠病学部将获得该奖项。为托马斯博士提供必要的支持来检验结肠炎是由扩张引起的假设将特定结肠 CD8+ T 驻留记忆 (Trm) 细胞转化为产生 IL-26 和 IL-17A 的细胞毒性效应细胞并直接归巢于受损的上皮，对上皮更新产生有害影响该假设将通过以下目标进行检验：（目标 1）定义表观遗传。不同结肠 CD8+ Trm 和 Trm 衍生效应器的景观和效应器功能（目标 2）确定是否血液中重新审视结肠炎患者结肠粘膜中检测到的 CD8+ T 效应细胞以及血液免疫细胞状态与疾病的关系；（目标 3）将 CD8+ Trms 和受损上皮细胞之间的相互作用映射到了解 PD-1 抑制如何导致 CD8+ Trm 归巢和上皮细胞中干扰素依赖性缺陷通过这些提出的目标，托马斯博士将绘制出吸收功能之间复杂的相互作用。 PD-1 阻断后的 CD8+ Trms 和受损的结肠上皮她将在她的指导下工作。主要导师 Nir Hacohen 博士是免疫肿瘤学和自身免疫领域的专家，她的共同导师 Dr. Nir Hacohen 是一位免疫肿瘤学和自身免疫学专家。 Alexandra-Chloé Villani，利用单细胞基因组学了解免疫异质性的专家拟议的实验、分析和教学工作将为托马斯博士提供一个关于健康和疾病的知识。一套独特的技能将使她能够作为一名研究免疫的医生科学家过渡到独立这些研究将确定 IL-26+ 和 IL-17A+ CD8+ T 介导的机制。细胞效应器协调病理性炎症，并将允许开发诊断工具和广泛适用于结肠炎患者和炎症性肠病患者的治疗策略到这个为期五年的奖项的第四年，Thomas 博士将有能力开发 R01 应用程序。确定人类胃肠道的病理 Trm 反应和治疗结肠炎的治疗靶点。