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疗法已大大改善了几个晚期患者的预后最初被认为终端的阶段癌症。但是，检查点抑制剂的使用增加具有导致免疫相关不良事件（IRAE）的普遍出现。即使他们通常是在临床实践中，不包括临床试验，提供了自身免疫性倾向的患者检查点抑制剂，并具有开发伊拉斯的最大风险。驱动这种免疫毒性的机制很差理解，甚至了解检查点抑制剂如何与容易发生的免疫系统相互作用的了解自身免疫性。由于恶性肿瘤是威胁生命的疾病，因此有未满足的医疗需要将检查点抑制剂抗肿瘤反应的自身免疫性毒性。我假设个人可以基于其遗传学和特定肠道微生物的结合而易于伊拉斯。在此提案中，我建立了一个反映自身免疫性倾向的新兴范式的小鼠模型和伊拉斯发展中的微生物组。我将使用ACT1 - / - 鼠标，这些鼠标会发展出赞助的系统性在特定的无病原体条件下，狼疮红斑和类似于Sjogren的自身免疫性疾病，具有升高老化后基线Th17和B细胞活性。用抗PD-1和抗CTLA-4抗体联合处理显着加快并加剧了自身免疫攻击的发作和严重性。在AIM 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效率。我也是确定GF ACT1 - / - 小鼠不容易受到IRAE发育的影响，这与越来越多的证据保持一致微生物组在定义对检查点抑制剂的响应性方面的关键作用以及缓解措施伊拉斯。在AIM 2中，我将检验以下假设：尽管ICI效率已与某些成员有关肠道微生物群社区，微生物的一个独特的子集可以允许在一般的敏感的主人。该提案中研究的机制可能被证明可用于临床的基础 ICI分娩之前，患者人群的基因筛查方法。