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、肾癌 细胞癌(RCC)占所有病例的90%。约25%的肾癌患者存在 初诊时转移，高达20%-30%的患者在确诊后出现复发 肾切除术。免疫疗法是中等风险一线治疗的一种新的护理标准选择 或风险较低的晚期肾癌患者。然而，免疫治疗的结果是不同的， 一些患者获得了完全缓解，另一些患者则完全没有受益。因此，重要的是要 确定有助于患者选择和风险分层的可修改因素和生物标记物，并 检测将经历与治疗相关的不良事件和疾病进展的患者。生长 有证据表明，肠道微生物群与癌症治疗的毒性有关，并可能调节反应。 为了癌症治疗。因此，我们建议1)鉴定和验证治疗前肠道微生物组图谱， 与循环T细胞激活相关的特定细菌种类和细菌功能途径与癌症 晚期肾癌患者的免疫治疗反应、不良事件和无进展生存； 2)确定和验证与癌症免疫治疗相关的肠道微生物群组和细菌的变化 功能通路及其与循环T细胞激活、癌症免疫治疗反应的关系 晚期肾癌患者的不良事件和无进展生存期，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；4)初步获得 按性别和种族划分的肠道微生物组概况、细菌功能途径和结果的数据。这个 研究结果将大大有助于我们理解肠道微生物群在癌症中的作用 免疫治疗的反应、疗效和不良反应，不仅与晚期肾细胞癌有关 患者，也适用于更大一组接受癌症免疫治疗的癌症患者，这被认为是 这是癌症治疗中最有希望的最新发展。

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.