Abstract
The advent of combination immune checkpoint inhibitors (cICI), specifically ipilimumab and nivolumab, has transformed the treatment landscape for metastatic renal cell carcinoma (mRCC), offering durable remissions and improved outcomes for intermediate- and poor-risk patients. However, intrinsic resistance remains a significant challenge, with 40-60% of patients failing to achieve meaningful responses. Here, we conducted a comprehensive, multi-omic analysis of systemic and tumor-associated immune responses in mRCC patients enrolled in a clinical trial (CA209-980, SAKK07/17, NCT03297593 ) testing a novel response-adapted cICI regimen. Our study aimed to identify immune correlates of response to cICI therapy. High-dimensional mass cytometry and single-cell proteomic and bulk RNA sequencing of the tumor revealed an enrichment of Th17 CD4+ T cells in responders. These cells exhibited upregulated IL-21-driven pathways, IL-17 signaling, and inflammasome-associated processes, highlighting their central role in therapeutic efficacy. Our integrative analysis underscores the importance of Th17 cells in mediating effective responses to cICI and provides a framework for developing predictive biomarkers and therapeutic strategies to overcome resistance. These findings highlight the translational potential of targeting Th17-centric pathways to enhance immunotherapy outcomes in mRCC and potentially other cancers. This work represents a significant step toward advancing personalized oncology through integrated immune profiling.