Project 1

项目1总结 我们假设宿主免疫反应和肠道微生物区系之间的相互作用影响疗效和 免疫检查点抑制(ICI)对黑色素瘤患者的毒性。越来越多的证据表明，直觉 微生物区系在调节癌症的先天和获得性免疫反应中起着重要作用。 免疫疗法。我们和其他人已经提供了令人信服的证据，表明肠道微生物群与 免疫治疗的疗效和毒性。我们还发现，新的基线预处理T细胞 表型与外周血中T调节细胞的水平和抑制功能有关 在PD-1阻断后，黑色素瘤患者的无复发生存率(RFS)增加。此外，我们发现，改变 在血清蛋白中，免疫通路与PD-1阻断导致的存活率降低有关，强调 宿主免疫反应对免疫治疗结果的重要性。然而，没有确定的、大规模的 人体研究已经确定了与阿司匹林的疗效和/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反应的关系。 项目1的目标是识别微生物和宿主免疫生物标记物，这些生物标志物可以预测阿司匹林的疗效和毒性 ICI在一项随机的III期佐剂试验中测试PD-1/CTLA-4联合阻断与PD-1单独使用 高危切除IIIB/C期和IV期黑色素瘤的患者。作为大规模、控制良好的随机调查的一部分 和盲法试验(n=2000；n=1500个可用的血液/粪便样本的子集)，我们将在 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中的作用，并检验其实用性 在这些生物标志物中预测免疫治疗的临床疗效和毒性(目标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益处的患者队列 从联合与单一特工检查站封锁(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 严格复制的生物标记物鉴定。 这项研究将通过定义预测性生物标志物和开发预测性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-这可以促进个性化免疫治疗 决定。最后，考虑到肠道细菌的可变性，这些发现可能会导致针对特定微生物的研究 改善ICI疗效和减轻其毒性的介入方法。

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.