Lenvatinib Targets FGFR4 to Enhance Antitumor Immune Response of Anti-PD-1 in Hepatocellular Carcinoma.

Background & aim Recently, the clinical trials of lenvatinib plus pembrolizumab in hepatocellular carcinoma (HCC) displayed an impressive objective response rate (ORR). This study aimed to clarify the mechanism for optimal patient selection. Approach & results First, in patients with HCC, lenvatinib-treated recurrent tumors had lower programmed death ligand 1 (PD-L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL/6 wild-type mice receiving anti-PD-1 therapy, PD-L1 expression and Treg infiltration in subcutaneous tumors reduced when adding lenvatinib to the scheme. Mechanistically, on one hand, fibroblast growth factor receptor 4 (FGFR4) was the most pivotal target in PD-L1 down-regulation by lenvatinib in vitro. Furthermore, lenvatinib reinforced the proteasomal degradation of PD-L1 by blocking the FGFR4-GSK3β axis and rescued the sensitivity of interferon-γ-pretreated HCC cells to T-cell killing by targeting FGFR4. On the other hand, the level of interleukin 2 (IL-2) increased after anti-PD-1 treatment, but IL-2-mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and tumor FGFR4 level in C57BL/6-Foxp3DTR (DEREG) mice, we found that high levels of FGFR4 and Tregs infiltration sensitized tumor to the combination treatment. Finally, high levels of FGFR4 and forkhead box protein P3 (Foxp3) conferred immune tolerance but better response to the combined therapy in patient cohorts. Conclusions Lenvatinib reduced tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4. Levels of FGFR4 expression and Tregs infiltration in tumor could serve as biomarkers for screening HCC patients with lenvatinib plus anti-PD-1 combination therapy.