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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.

项目摘要免疫检查点抑制剂治疗显著改善了几种晚期癌症患者的预后。最初被认为是晚期癌症的晚期癌症。然而，检查点抑制剂的使用增加了导致免疫相关不良事件(IrAEs)的普遍出现。即使他们通常是排除在临床试验之外，在临床实践中，有自身免疫易感性的患者被提供检查点抑制剂，并有最大的风险发展irAEs。驱动这种免疫毒性的机制很差。了解，而关于检查点抑制剂如何与免疫系统相互作用更是知之甚少自身免疫力。由于恶性肿瘤是威胁生命的疾病，因此有一种尚未得到满足的医学需求，即与癌症脱钩检查点抑制物抗肿瘤反应的自身免疫毒性。我假设每个人都可以根据他们的基因和特定的肠道微生物的组合而容易感染irAEs。在这份提案中，我建立了一个小鼠模型，它反映了自身免疫易感性的新兴范式和 IrAEs发育过程中的微生物组。我将使用Act1-/-小鼠，它会发展成自发的系统性红斑狼疮和干燥样自身免疫性疾病在无特定病原体的条件下升高衰老后基线Th17和B细胞活性。抗PD-1和抗CTLA-4抗体联合治疗大大加速和加剧了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-/-小鼠体内驱动irAEs，同时仍保持检查点抑制物的有效性。我也是确定了GF Act1-/-小鼠对IRAE发育不敏感，这与越来越多的证据相一致微生物组在确定对检查点抑制剂的反应性以及缓解这就是我们的工作。在目标2中，我将测试这一假设，即虽然ICI的疗效与肠道微生物群落，一个不同的微生物亚群可以允许在基因上诱导irAEs 易感宿主。这项建议中研究的机制可能被证明对临床上 ICI分娩前患者群体的基因筛查方法。