Gut Microbiome and Cancer Immunotherapy Outcomes in Advanced Renal Cell Carcinoma

摘要 到2021年，美国将有大约76，080人被诊断出患有肾癌，其中肾功能衰竭的患者将超过20%。 细胞癌（RCC）占所有病例的>90%。大约25%的RCC患者存在以下症状： 在最初诊断时，肿瘤转移，并且高达20-30%的患者在 肾切除术免疫治疗是一种新的标准治疗选择，用于中等风险的一线治疗。 或晚期肾癌的低风险患者。然而，免疫治疗的结果是异质的， 一些患者达到完全缓解，而另一些患者根本没有获益。因此， 确定可改变的因素和生物标志物，有助于患者选择和风险分层， 检测将发生治疗相关不良事件和疾病进展的患者。增长 证据支持肠道微生物组有助于癌症治疗毒性，并可能调节反应 到癌症治疗因此，我们建议1）识别和验证治疗前肠道微生物组谱， 特定的细菌种类和与循环T细胞活化相关的细菌功能途径， 晚期肾细胞癌患者的免疫治疗反应、不良事件和无进展生存期; 2)确定和验证肠道微生物组谱和细菌中与癌症免疫治疗相关的变化 功能途径，以及它们与循环T细胞活化，癌症免疫治疗反应， 不良事件和晚期RCC患者的无进展生存期，3）探讨 细菌代谢产物和相关生物标志物在癌症免疫治疗反应中的作用，以及4）获得初步的 按性别和种族分列的肠道微生物组概况和细菌功能途径及结果的数据。的 研究结果将大大有助于我们理解肠道微生物组在癌症中的作用。 免疫治疗反应、疗效和不良事件，不仅与晚期RCC相关， 患者，但也适用于接受癌症免疫疗法治疗的更大群体的癌症患者，这被认为是 是癌症治疗中最有前途的新进展。

ABSTRACT In 2021, approximately 76,080 individuals in the United States will be diagnosed with kidney cancer, with renal cell carcinoma (RCC) accounting for >90% of all cases. Approximately 25% of patients with RCC present with metastasis at the time of initial diagnosis and up to 20-30% of patients develop recurrent disease after nephrectomy. Immunotherapy is a new standard-of-care option for the first-line treatment of intermediate-risk or poor-risk patients with advanced RCC. However, the immunotherapy outcomes are heterogeneous, with some patients achieving a complete remission, and others having no benefit at all. Therefore, it is important to identify modifiable factors and biomarkers that could help with patient selection and risk stratification, and to detect patients who will experience treatment-related adverse events and disease progression. Growing evidence supports that the gut microbiome contributes to cancer therapy toxicities and may modulate response to cancer therapy. Therefore, we propose to 1) identify and validate pre-treatment gut microbiome profiles, specific bacterial species, and bacterial functional pathways associated with circulating T-cell activation, cancer immunotherapy response, adverse events, and progression-free survival among patients with advanced RCC; 2) identify and validate cancer immunotherapy-associated changes in the gut microbiome profiles and bacterial functional pathways, and their association with circulating T-cell activation, cancer immunotherapy response, adverse events, and progression-free survival among patients with advanced RCC, 3) explore the role of bacterial metabolites and related biomarkers in cancer immunotherapy response, and 4) obtain preliminary data on the gut microbiome profiles and bacterial functional pathways and outcomes by sex and race. The study results will contribute considerably to our understanding of the role of the gut microbiome in cancer immunotherapy response, efficacy, and adverse events, and will be relevant not only for advanced RCC patients, but also for a larger group of cancer patients treated with cancer immunotherapy, which is considered to be most promising recent development in cancer therapy.