Multi-omic profiling reveals key drivers of response to dual CTLA-4/PD-1 immunotherapy in mRCC 4681

Abstract Description Background. Therapeutic options for metastatic renal cell carcinoma (mRCC) have improved, but patients with intermediate and poor-risk disease, comprising ∼75% of advanced RCC cases, face worse outcomes. Combination immunotherapy (cICI) targeting PD-1 and CTLA-4 shows a survival advantage and durable remissions in these patients compared to monotherapies. However, cICI also causes severe immune-related adverse events and fails in 40–60% of cases. Unlike other cancers, CD8+ T-cell infiltration in RCC does not correlate with improved prognosis or treatment responses, highlighting gaps in understanding immune signatures linked to long-term response. Methods and results. Using mass cytometry, bulk RNA sequencing, and single-cell RNA sequencing (Cite-seq), we profiled immune responses in peripheral blood and tumors from 72 mRCC patients treated with cICI. Bulk RNASeq revealed enriched CD4+ naïve and memory T cells, Th17 and Th2 signatures, and cytokines IL-2, IL-4, IL-5, IL-13, and IFN-γ in the tumor microenvironment (TME) of responders. Imaging mass cytometry confirmed these findings at the protein level, showing cellular composition and spatial interactions in primary tumors and metastases. Ongoing studies with Cite-seq and mass cytometry aim to identify these RNA signatures in peripheral blood pre-therapy. Conclusions. Th2 and Th17 responses may predict ICI response in poor-risk mRCC, offering a tool for better patient stratification and treatment assignment. Funding Sources American Cancer Society RSG-24-1255025-01-IBCD NIH/NCI R01 CA258882 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)