Gut Microbiome and Cancer Immunotherapy Outcomes in Advanced Renal Cell Carcinoma

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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.