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

项目摘要 抗共抑制性免疫受体PD-1和CTLA-4的单抗[免疫检查点抑制物 (ICIS)]通过逆转T细胞衰竭和利用T细胞的力量，使免疫肿瘤学发生了革命性的变化 免疫系统来对抗实体瘤。尽管ICI治疗提高了转移性心脏病患者的存活率 对于癌症，不幸的是，治疗受到与免疫相关的不良事件发展的限制。结肠炎是 ICIS最常见、最严重的副作用--在服用PD-1的患者中有5%-10%出现，在服用PD-1的患者中高达50% 双重PD-1/CTLA-4被阻断，并以上皮损伤和细胞凋亡为标志。到目前为止，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。 开发计划侧重于了解PD-1后发生的人类结肠炎的免疫驱动因素 封锁[即与免疫治疗相关的结肠炎(IrColtis)]。莫莉·托马斯博士是哈佛大学的医学讲师。 哈佛医学院在马萨诸塞州总医院的胃肠病学部。这一奖项将 为托马斯博士提供必要的支持，以检验肠炎是由扩张引起的这一假说 将特定的结肠CD8+T-驻留记忆(Trm)细胞转化为产生IL-26和IL-17A的细胞毒效应细胞 并直接导致受损的上皮细胞，在那里它们对上皮细胞的周转和 吸收功能。这一假说将通过以下目标进行检验：(目标1)定义表观遗传学 不同的结肠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 肠炎患者结肠黏膜中检测到CD8+T细胞效应分子在血液中循环及血液免疫 细胞状态跟踪疾病；(目标3)映射CD8+TRMS与受损的上皮细胞之间的相互作用 了解PD-1抑制如何导致CD8+Trm归巢和上皮细胞干扰素依赖性缺陷 吸收功能。通过这些提出的目标，托马斯博士将绘制出复杂的相互作用 PD-1阻断后CD8+TRMS和结肠上皮损伤。她将在她的指导下工作 主要导师尼尔·哈科恩博士是一位免疫肿瘤学和自身免疫方面的专家，她的另一位导师尼尔·哈科恩博士。 Alexandra-ChloéVillani，一位利用单细胞基因组学了解人类免疫异质性的专家 健康和疾病。拟议的实验、分析和教学工作将为托马斯博士提供一个 一套独特的技能，使她能够过渡到独立成为一名研究免疫的内科科学家- 引发胃肠道疾病。这些研究将确定IL-26+和IL-17A+CD8+T细胞的机制 细胞效应器协调病理性炎症，并将允许开发诊断工具和 广泛适用于肠炎患者和炎症性肠病患者的治疗策略 疾病。到这个为期五年的奖项的第四年，托马斯博士将处于开发R01应用程序的有利地位 明确人类胃肠道的病理性Trm反应和治疗肠炎的靶点。

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.