Immune response and resistance of clear cell renal cell carcinoma patients following immune checkpoint blockade

175,000 patients die because of renal cell carcinoma (RCC) each year. Clear cell renal cell carcinoma (ccRCC or KIRC) is the most frequent subtype of RCC. Current therapies include immune checkpoint inhibitors (ICB) or VEGFR tyrosine kinase inhibitors (TKIs). However, many patients did not respond to ICB and immune resistance still occurred. Immune resistance may be explained by expression of various immune checkpoints and immunosuppressive pathways in KIRC patients. Thus, it is important to identify mechanisms driving immune response and resistance following ICB. To address this question, we performed an analysis of 3 KIRC cohorts treated with 3 different ICB. Overall, 20-30% of KIRC patients respond to ICB. Responders with metastasized stage IV cancer with tumorectomy prior to anti-PD-L1 are characterized by an increase in CD4+ and CD8+ T cell infiltration, and by better antigen presentation and T cell responses ( BTN3A1, PRF1 and CD27 genes). However, the expression of CTLA4, TIGIT and BTLA in Th1, Th17 and M2 subsets may limit complete response in responders. Importantly, non-responders patients are characterized by higher infiltration by macrophages, and by overexpression of regulatory gene ( ADORA2A ) in Th2, CD8+ T cell, M1 and M2 clusters. Targeting these pathways may help to develop combination therapies to improve KIRC patient outcomes.