Efficacy of immune checkpoint inhibitors in advanced Renal Cell Carcinoma resistance to anti-angiogenic inhibitors. Susmita Ghosh1, Mamatha Garige1, Uma T. Shankavaram2, Carole Sourbier1 1Office of Biotechnology Products, OPQ, CDER ; 2Radiation Oncology Branch, NCI, NIH Sunitinib, a VEGFR tyrosine kinase inhibitor, has been approved as first-line therapy for patients with advanced renal cell carcinoma (RCC) for over a decade. However, patients who receive sunitinib treatment gradually acquire resistance to the drug. Recently, immune checkpoint inhibitors (ICIs) have been approved as a second-line therapy for individuals with RCC who developed a resistance to anti-angiogenic therapies. It remains however unknown how ICIs efficacy is affected by the development of resistance to anti-angiogenic inhibitors. Thus, our goals are (1) to develop and characterize an RCC model of resistance to sunitinib and (2) to compare the efficacy of ICIs between naïve and sunitinib-resistant RCC. We established 2 RCC cell lines resistant to sunitinib. Characterization of these cell lines demonstrated an acquired resistance to sunitinib in vitro by viability assays. Consistent with the literature, sunitinib-resistant RCC cell lines presented an aberrant over-expression of Axl and PDL1 , as well as a decreased activation of the STAT3 pathway and of LDHA, compared to the parental cell lines. Metabolomics and transcriptomics analyses following treatment of the sunitinib-resistant RCC cells with ICIs in vitro revealed that ICIs induced a metabolic rewiring of RCC cell lines characterized by enhanced OXPHOS and glutamine metabolism. This metabolic rewiring of sunitinib-resistant RCC cells following ICIs’ treatment is consistent with what was observed in the tumors of patients who benefited from ICIs therapy. Therefore, these data suggest that sunitinib-resistance might be supportive of ICIs’ efficacy in advanced RCC. To confirm this hypothesis, co-culture and animal experiments are on-going. This study will advance our understanding of the mechanism of action of ICIs and of how tumors respond to immunotherapies. Our long-term goal is to utilize tumor metabolism as a tool to predict therapeutic efficacy by identifying critical product quality attributes of therapeutic monoclonal antibodies.