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

• 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
• 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' 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

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 最初被认为是晚期的癌症。然而，检查点抑制剂的使用增加 导致免疫相关不良事件（irAE）的普遍出现。尽管他们通常是 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。 自身免疫。由于恶性肿瘤是危及生命的疾病，因此脱钩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。我假设个人可以 基于其遗传学和特定肠道微生物的组合，他们易患 irAE。在这个提案中， 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，它们会自发产生系统性的 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。我也 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 irAE。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 易感宿主。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。