Immunomodulatory Roles of VEGF Pathway Inhibitors in Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs) in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become a new standard of care in treatment-naive patients with advanced renal cell carcinoma (RCC). The rationale for these combinations relies on the interplay between the immune and angiogenic systems. The angiogenic factors and their receptors can promote an immunosuppressive tumor microenvironment by a direct effect on the innate immune cells and adaptive immune cells, and by an indirect effect through their influence on endothelial cells. Antiangiogenic therapies counteract these immunosuppressive effects by increasing tumor infiltration of mature dendritic cells and effector T cells, and decreasing tumor infiltration of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. The immunomodulatory properties of antiangiogenic therapies combined with ICIs may provide enhanced activity through various mechanisms of action. Different associations with ICIs such as programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors and antiangiogenic therapies such as VEGFR-TKI or bevacizumab have been tested and led to the approval of pembrolizumab plus axitinib and avelumab plus axitinib in the first-line treatment of patients with advanced RCC. Other VEGFR axis inhibitors and ICI combinations are currently being tested with promising results. More combinations of immune agents, including cancer vaccines and immunostimulatory agents, are also being evaluated in association with VEGFR-TKI. Defining the best combination for each patient as well as the optimal therapeutic sequence will be essential to guide treatment decisions in clinical practice.