Project 1

项目1概要 我们假设宿主免疫反应和肠道微生物群之间的相互作用影响了疗效， 免疫检查点抑制（ICI）在黑素瘤患者中的毒性。越来越多的证据表明， 微生物群在调节对癌症的先天性和适应性免疫应答中起重要作用。 免疫疗法我们和其他人已经提供了令人信服的证据，表明肠道微生物组与 免疫疗法的疗效和毒性。我们还表明，新的基线治疗前T细胞 外周血中调节性T细胞的水平和抑制功能与表型相关 在黑色素瘤中PD-1阻断后无复发生存期（RFS）增加。此外，我们发现， 血清蛋白免疫途径与PD-1阻断后生存率降低相关， 宿主免疫应答对免疫治疗结果的重要性。尽管如此，没有明确的，大规模的 人类研究已经鉴定了与药物的功效和/或毒性相关的肠道微生物分类群 免疫疗法，也没有研究它们与宿主免疫应答的关系。 项目1的目标是鉴定微生物和宿主免疫生物标志物，以预测 ICI在一项随机III期辅助试验中测试PD-1/CTLA-4阻断联合治疗与PD-1单药治疗相比， IIIB/C期和IV期黑色素瘤高风险切除患者。作为一项大型、对照良好的随机 和盲法试验（n=2000; n=1500个可用血液/粪便样本的子集），我们将评估肠道微生物群， 粪便和一系列创新的生物标志物在血清和外周血免疫细胞，并检查效用 这些生物标志物来预测来自免疫疗法的临床功效和毒性（目的1和2）。基于 整合这些生物标志物，我们将额外定义可能获得不同获益的患者队列 从组合与单剂检查点阻断（目标3）。这项研究基于一项大型临床试验， 标准化的治疗和临床结果以及毒性评估，将为 生物标志物鉴定与严格的重复。 这项研究将通过定义预测性生物标志物和开发预测分类器来改善患者护理 - 使用容易获得的粪便，血清和血液样本-可以促进个性化免疫治疗 决策最后，考虑到肠道细菌的可变性，研究结果可能会导致定制的微生物靶向治疗。 介入方法，以提高疗效，并减轻毒性，ICI。

PROJECT 1 SUMMARY We hypothesize that interplay between host immune responses and the gut microbiota affect the efficacy and toxicity of immune checkpoint inhibition (ICI) in melanoma patients. Increasing evidence suggests that gut microbiota play important roles in regulating the innate and adaptive immune response to cancer immunotherapy. We and others have provided compelling evidence that the gut microbiome is associated with the efficacy and the toxicity of immunotherapy. We also showed that novel baseline pre-treatment T-cell phenotypes and the levels and suppressive function of T regulatory cells in the peripheral blood were associated with increased relapse-free survival (RFS) after PD-1 blockade in melanoma. Moreover, we found that alterations in serum protein immune pathways were associated with decreased survival with PD-1 blockade, underlining the importance of host immune responses for immunotherapy outcomes. Nonetheless, no definitive, large scale human studies have identified the gut microbial taxa associated with the efficacy and/or toxicity of immunotherapy, nor investigated their relationships with host immune responses. The goal of Project 1 is to identify microbial and host immune biomarkers that predict the efficacy and toxicity of ICI in a randomized phase III adjuvant trial testing combination PD-1/CTLA-4 blockade versus PD-1 alone in patients with high-risk resected stage IIIB/C and IV melanoma. As part of a large, well-controlled randomized and blinded trial (n=2000; a subset of n=1500 available blood/stool samples), we will evaluate gut microbiota in stool and a series of innovative biomarkers in serum and peripheral blood immune cells, and examine the utility of these biomarkers to predict clinical efficacy and toxicity from immunotherapy (Aims 1 and 2). Based on integration of these biomarkers, we will additionally define cohorts of patients who may derive differential benefit from combination versus single-agent checkpoint blockade (Aim 3). This study, based on a large clinical trial with standardized treatments and clinical outcome as well as toxicity assessments, will provide excellent power for biomarker identification with rigorous replications. This research will improve patient care by defining predictive biomarkers and developing a predictive classifier – using easily obtainable stool, serum, and blood samples – that can facilitate personalized immunotherapy decisions. Finally, given the modifiable nature of gut bacteria, findings could lead to tailored microbe-targeted interventional approaches to improve the efficacy of, and attenuate the toxicity of, ICI.