Host and microbe-dependent mechanisms of enhanced autoimmune susceptibility driven by checkpoint inhibitors

检查点抑制剂驱动的增强自身免疫易感性的宿主和微生物依赖性机制

基本信息

批准号：
10750805
负责人：
Vanessa Salazar
金额：
$ 5.27万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2023-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750805
关键词：
Abdomen Aging Antibodies Antitumor Response Apoptosis Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Cell Activation B-Lymphocytes Bacteria Biological Models CD19 gene CD3 Antigens CT26 Cells Chronic Clinical Clinical Trials Colon Adenocarcinoma Combined Modality Therapy Communities Control Groups Cytotoxic T-Lymphocytes Data Deposition Development Disease Evaluation Exclusion Fatty acid glycerol esters Foundations Generations Genetic Genetic Predisposition to Disease Genetic Screening Germ-Free Goals Greater sac of peritoneum Histologic Homeostasis Human Immune Immune checkpoint inhibitor Immune system Immunoglobulin G Immunologics Impairment Incidence Individual Infiltration Intestines Lead Life Link Lymphocyte antigen Malignant Neoplasms Mediating Medical Medical Genetics Mesentery Microbe Modeling Mus Pancreas Patient Care Patients Peritoneal Pre-Clinical Model Predisposition Psoriasis Risk Role Severities Signal Transduction Single Nucleotide Polymorphism Sjogren&apos s Syndrome Systemic Lupus Erythematosus T-Lymphocyte TNFRSF5 gene Testing Therapeutic Uses Tissues Toxic effect Wild Type Mouse aged autoimmune pathogenesis autoimmune toxicity cancer immunotherapy checkpoint inhibition checkpoint therapy clinical practice experimental study germ free condition gut microbes gut microbiota immune activation immune cell infiltrate immune-related adverse events immunopathology improved member microbiome microbiome components microbiota mouse model patient population patient prognosis permissiveness response success tumor

项目摘要

Project Summary Immune checkpoint inhibitor therapy has drastically improved the prognosis of patients with several advanced- stage cancers that were initially considered terminal. However, the increased use of checkpoint inhibitors has resulted in the common emergence of immune-related adverse events (irAEs). Even though they are typically excluded from clinical trials, in clinical practice, patients with autoimmune predisposition are offered checkpoint inhibitors and have the greatest risk for developing irAEs. The mechanism driving this immune toxicity is poorly understood, and even less is known about how checkpoint inhibitors interact with immune systems prone to autoimmunity. Since malignancies are life-threatening diseases, there is an unmet medical need to decouple autoimmune toxicities from checkpoint inhibitor antitumor response. I hypothesize that individuals can be predisposed to irAEs based on a combination of their genetics and specific gut microbes. In this proposal, I established a mouse model that reflects the emerging paradigm of autoimmune predisposition and the role of the microbiome in the development of irAEs. I will use the Act1-/- mice, which develop spontaneous systemic lupus erythematous and Sjogren-like autoimmune diseases in specific pathogen free conditions with elevated baseline Th17 and B cell activity after aging. Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies significantly expedited and exacerbated the onset and severity of autoimmune attack. In Aim 1, I will test the hypothesis that B cells drive irAEs in Act1-/- mice while still maintaining checkpoint inhibitor efficacy. I also determined that GF Act1-/- mice are not susceptible to irAE development, which aligns with the growing evidence of the microbiome’s critical role in defining responsiveness to checkpoint inhibitors as well as the mitigation of irAEs. In Aim 2, I will test the hypothesis that while ICI efficacy has been linked to certain members of the intestinal microbiota community, a distinct subset of microbes can allow for the induction of irAEs in a genetically susceptible host. The mechanisms studied in this proposal may prove useful for the foundation of a clinical genetic screening approach for the patient population prior to ICI delivery.

项目概要免疫检查点抑制剂治疗显着改善了多种晚期患者的预后然而，检查点抑制剂的使用增加已经使最初被认为是晚期的癌症得以治愈。导致免疫相关不良事件（irAE）的常见出现，尽管它们通常是常见的。排除在临床试验之外，在临床实践中，为具有自身免疫倾向的患者提供检查点抑制剂，并且发生 irAE 的风险最大。驱动这种免疫毒性的机制很差。人们对检查点抑制剂如何与免疫系统相互作用知之甚少。由于恶性肿瘤是危及生命的疾病，因此解耦的医疗需求尚未得到满足。检查点抑制剂抗肿瘤反应产生的自身免疫毒性我认为个体可能是这样的。根据其遗传学和特定肠道微生物的组合，易患 irAE。我建立了一个小鼠模型，该模型反映了自身免疫倾向的新兴范式以及 irAE 发展中的微生物组我将使用 Act1-/- 小鼠，它们会自发地产生全身性症状。在特定的无病原体条件下，红斑狼疮和干燥样自身免疫性疾病的发病率升高衰老后的基线 Th17 和 B 细胞活性抗 PD-1 和抗 CTLA-4 抗体联合治疗。显着加速并加剧自身免疫攻击的发生和严重程度在目标 1 中，我将测试假设 B 细胞在 Act1-/- 小鼠中驱动 irAE，同时仍保持检查点抑制剂功效。确定 GF Act1-/- 小鼠不易受到 irAE 的影响，这与越来越多的证据相一致微生物组在定义对检查点抑制剂的反应以及缓解在目标 2 中，我将检验以下假设：虽然 ICI 功效与某些成员有关。肠道微生物群落是一个独特的微生物子集，可以在基因上诱导 irAE 该提案中研究的机制可能对临床基础有用。 ICI 交付前对患者群体进行基因筛查的方法。