Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma

Abstract Although immune checkpoint inhibitors can lead to “exceptional”, durable clinical responses in a subset of patients, the molecular mechanisms underlying exceptional responses (ERs) are still unknown. We analyzed pre-therapy genomic and transcriptomic data in treatment-naive patients with mccRCC treated with standard-of-care immunotherapies: (1) combination of PD-1/PDL1 and CTLA-4 (IO/IO), or (2) PD-1/PD-L1 inhibitor and VEGF-receptor inhibitor (IO/VEGF) combination. In the IO/IO cohort, clonal neoantigen load was significantly higher in ER patients. In the IO/VEGF cohort, ER patients displayed strong enrichment of B-cell receptor signaling related pathways, tertiary lymphoid structure (TLS) signatures, and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T-cell responses and TLS formation in tumor microenvironments. We conclude that novel therapeutic combinations that elicit both T- and B-cell directed anti-tumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.