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.

项目摘要 免疫检查点抑制剂治疗已经大大改善了几种晚期- 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）的常见出现。尽管他们通常 从临床试验中排除，在临床实践中，为具有自身免疫易感性的患者提供检查点 抑制剂，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的了解更少， 自身免疫由于恶性肿瘤是危及生命的疾病，因此， 来自检查点抑制剂抗肿瘤反应的自身免疫毒性。我假设个人可以 根据其遗传学和特定肠道微生物的组合，易患irAE。在这项提案中， 我建立了一个小鼠模型，该模型反映了自身免疫易感性的新范式以及 微生物组在irAE发展中的作用。我将使用Act 1-/-小鼠， 狼疮性和干燥样自身免疫性疾病在无特定病原体的条件下， 老化后基线Th 17和B细胞活性。抗PD-1和抗CTLA-4抗体的联合治疗 显著加速和加剧自身免疫性攻击的发作和严重程度。在目标1中，我将测试 假设B细胞在Act 1-/-小鼠中驱动irAE，同时仍维持检查点抑制剂功效。我也 确定GF Act 1-/-小鼠对irAE发展不敏感，这与越来越多的证据一致 微生物组在定义对检查点抑制剂的反应性以及缓解 irAE。在目标2中，我将检验一个假设，即虽然ICI的疗效与某些成员有关， 肠道微生物群，一个独特的微生物亚群可以允许在遗传学上诱导irAE。 易感宿主在这项建议中研究的机制可能被证明是有用的基础上，临床 在ICI递送之前对患者群体的遗传筛查方法。