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

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。

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.