Abstract 2687: Exploring the synergistic mechanisms of VEGFR and immune checkpoint inhibitors in clear cell renal cell carcinoma metastases

Abstract M.C. and E.D. equally contributed. Clear cell renal cell carcinoma (ccRCC) is the most common malignancy originated from the kidney, with bone and lungs as the main sites of distant spread in vast majority of patients. A key feature of ccRCC is the loss of function of the von Hippel-Lindau (VHL) protein leading to enhanced angiogenesis; in addition, ccRCC exhibits a rich and heterogeneous immune infiltrate. Consequently, different anti-angiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)have emerged as standard of care for these patients, as single agents or in combination. Yet, limited data are available on their efficacy in different metastatic sites, and their impact on the immune infiltrate is unclear. We hypothesized that modulation of the microenvironment with a TKI provides an additive impact on ICI, and the outcome of combinational treatments depends on metastatic sites, treatment doses and tumor size. To this purpose, we implanted a luciferase-GFP-positive RENCA-VHL- cell line in the tibia of immunocompetent mice, resulting in synchronous bone and lung metastases. Cabozantinib (C), as one of the most potent TKIs, anti-programmed cell death protein 1 (Anti-PD1) and anti-CTLA4 antibodies, were used as single agents or in combination. The outcomes were monitored by macroscopic bioluminescence detection in vivo, and 3D multiparametric spatial analysis of bones and lungs, ex vivo. Compared to control-treated mice, all agents significantly reduced tumor progression at both tumor sites. Although all these treatments are clinically applied at stage IV of disease development, differences in their efficacy were noted once treatment was withdrawn. Spatial analysis of tumor cells, immune infiltrate and blood vessels revealed significant changes dependent on treatment, tumor site and time, with potential synergistic mechanism by TKIs when used in combination with ICI. We proved the efficacy of standard of care for bone and lung lesions of ccRCC in an immunocompetent mouse model and identified differences between treatments at the cellular level in the tumor microenvironment. We believe our studies may provide important insights and efficacy predictions for therapeutic applications in metastatic ccRCC patients. Citation Format: Stefan Maksimovic, Nina Costanza Boscolo, Matthew T. Campbell, Eleonora Dondossola. Exploring the synergistic mechanisms of VEGFR and immune checkpoint inhibitors in clear cell renal cell carcinoma metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2687.