Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies.

Combination therapies consisting of immune checkpoint inhibitors plus anti-vascular endothelial growth factor (VEGF) therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGF receptor (VEGFR) and FGFR. Here, we examine the antitumor activity of anti-PD-1 monoclonal antibody (mAb) combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single-agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow-cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of interferon (IFN) γ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb.