Role of the Gut Microbiota in Regulating Responses to anti-PD-1 Cancer Immunotherapy

项目摘要 肠道共生被认为会影响人类健康和疾病的许多方面。是 现在被广泛接受的是，肠道微生物对肠道中的免疫稳态具有至关重要的影响。 新出现的证据表明，肠道微生物群塑造了全身免疫力，但其潜在机制 我们对此知之甚少。其他研究小组的最新报告和我们的初步发现表明， 微生物组及其组成是决定对免疫检查点反应性的重要因素 封锁1-3免疫检查点抑制剂是一种新的治疗干预措施， 特异性T细胞通过靶向T细胞中的共抑制途径攻击肿瘤细胞，如PD-1：PD-L1和 CTLA-4尽管这些检查点阻断免疫疗法在临床上取得了成功，但仍有相当大一部分人认为， 患者对检查点抑制剂没有反应4.最近的研究表明， 对检查点阻断的响应性的决定因素可能是肠道微生物组的组成。 然而，肠道微生物群如何调节对肿瘤的全身免疫反应尚不清楚。的目标 该项目旨在确定肠道微生物组调节抗肿瘤免疫的机制， 对PD-L1阻断的反应。为了实现这些目标，我们将1）使用gnotobiotic技术和抗生素， 鉴定在PD-L1阻断抗体治疗后促进肿瘤清除的人肠道微生物; 2） 阐明肠道微生物群依赖的抗肿瘤免疫的细胞和分子机制，重点是 肠道微生物群的变化如何控制调节抗肿瘤免疫的共抑制途径;以及3） 研究来自肠道的微生物产物如何有助于抗肿瘤免疫。拟定的研究将 为肠道微生物群调节抗肿瘤免疫的机制提供了重要的见解， 对PD-1通路阻断无应答的患者的治疗策略。

Project Summary Commensalism in the gut has been suggested to influence many aspects of human health and diseases. It is now widely accepted that gut commensal microbes have a crucial impact on immune homeostasis in the gut. Emerging evidence suggest that the gut microbiota shapes systemic immunity, but the underlying mechanisms are poorly understood. Recent reports from other groups and our preliminary findings indicate that the gut microbiome and its composition are important factors that determine responsiveness to immune checkpoint blockade 1-3. Immune checkpoint inhibitors are novel therapeutic interventions which reinvigorate tumor- specific T cells to attack tumor cells by targeting co-inhibitory pathways in T cells, such as PD-1:PD-L1 and CTLA-4. Despite the clinical success of these checkpoint blockade immunotherapies, a significant fraction of patients do not respond to the checkpoint inhibitors 4. Recent studies showed that one of the critical determinants of responsiveness to checkpoint blockade may be the composition of the gut microbiome. However, how the gut microbiota modulates systemic immune responses to tumor is not known. The goals of this project are to determine mechanisms by which the gut microbiome regulates anti-tumor immunity and response to PD-L1 blockade. To achieve these goals, we will 1) Use gnotobiotic techniques and antibiotics to identify human gut microbes that promote tumor clearance upon PD-L1 blocking antibody treatment; 2) elucidate cellular and molecular mechanisms of gut microbiota dependent anti-tumor immunity, focusing on how changes in the gut microbiota controls co-inhibitory pathways that regulate anti-tumor immunity; and 3) investigate how microbial products from the gut contribute to anti-tumor immunity. The proposed study will provide critical insights into mechanisms by which the gut microbiota regulates anti-tumor immunity, and new therapeutic strategies for patients who do not respond to PD-1 pathway blockade.