Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti–Programmed Cell Death‐1 in HCC

作者：Chenhe Yi, Lirong Chen, Zhifei Lin, Lu Liu, Weiqing Shao, Rui Zhang, Jing Lin, Jubo Zhang, Wenwei Zhu, Huliang Jia, Lun–Xiu Qin, Lu Lu, Jinhong Chen · 发表于：Hepatology · 年份：2021 · DOI：10.1002/hep.31921 · 被引用次数：298 · 研究领域：Fibroblast Growth Factor Research、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

Background and Aims Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection. Approach and 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–programmed cell death 1 (PD‐1) therapy, PD‐L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF 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–glycogen synthase kinase 3β 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 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 the tumor FGFR4 level in C57BL/6–forkhead box protein P3 ( Foxp3DTR ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high...