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

项目摘要 抗共抑制免疫受体PD-1和CTLA-4的单克隆抗体[免疫检查点抑制剂 （ICI）]通过逆转T细胞耗竭和利用免疫抑制剂的力量， 免疫系统对抗实体瘤。尽管ICI治疗改善了转移性肝癌患者的生存率， 不幸的是，癌症的治疗受到免疫相关不良事件的发展的限制。结肠炎是 ICI最常见的严重副作用-在PD-1治疗的5-10%患者和高达50%的PD-1治疗患者中观察到， 双重PD-1/CTLA-4阻断-并以上皮损伤和凋亡为标志。迄今为止， 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 抗体不容易产生胃肠道毒性。这份提案提出了一个为期五年的研究生涯 开发计划专注于了解PD-1后发展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）]。博士莫莉托马斯是一个医学讲师在 哈佛医学院马萨诸塞州总医院消化科。这个奖项将 为托马斯博士提供必要的支持，以检验irColitis是由扩张引起的假设 特异性结肠CD 8 + T驻留记忆（Trm）细胞转化为产生IL-26和IL-17 A的细胞毒性效应子 并直接归巢于受损的上皮，在那里它们对上皮更新具有有害影响， 吸收功能这一假设将通过以下目标进行测试：（目标1）定义表观遗传 不同的结肠CD 8 + Trm和Trm衍生的效应物的景观和效应物功能;（目的2）确定 免疫性结肠炎患者结肠黏膜中检测到CD 8 + T效应细胞存在于血液循环中， 细胞状态跟踪疾病;（目的3）绘制CD 8 + Trms和受损上皮细胞之间的相互作用， 了解PD-1抑制如何导致CD 8 + Trm归巢和上皮细胞中的干扰素依赖性缺陷 吸收功能通过这些提出的目标，托马斯博士将绘制复杂的相互作用之间 PD-1阻断后CD 8 + Trms和受损结肠上皮。她将在她的指导下工作 主要导师Nir Hacohen博士，免疫肿瘤学和自身免疫学专家，和她的共同导师Dr。 Alexandra-Chloé Villani是利用单细胞基因组学来了解免疫异质性的专家， 健康和疾病。拟议的实验，分析和教学工作将提供博士。托马斯 一套独特的技能，这将使她能够过渡到独立作为一个物理学家，科学家研究免疫， 介导的胃肠道疾病。这些研究将确定IL-26+和IL-17 A + CD 8 + T细胞介导的免疫应答的机制。 细胞效应器协调病理性炎症，并将允许诊断工具的发展， 治疗策略将广泛适用于irColitis患者和炎症性肠病患者 疾病到这个为期五年的奖项的第四年，托马斯博士将有能力开发R 01应用程序 以确定人类胃肠道中的病理性Trm反应和治疗irColitis的治疗靶点。

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.