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

Abstract

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 antiprogrammed 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 interferonγ-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 (Foxp3 DTR ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and 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 Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti-PD-1 combination therapy. (Hepatology 2021;74:2544-2560). H CC, the major primary liver cancer, is the fourth most common cause of cancer-related deaths worldwide. (1) HCC is usually diagnosed in advanced stages, resulting in limited treatment options. (2) Recently, the clinical success of immune checkpoint blockade (ICB) has been encouraging for patients with cancer. ICB works primarily by targeting cytotoxic lymphocyte antigen 4, programmed cell death protein 1 (PD-1), or programmed death ligand 1 (PD-L1). Anti-PD-1, as the most promising immunotherapy strategy, has the potential to elicit durable control and even cure of some treatment-refractory cancers,

Multi-Omics Analysis of the Anti-tumor Synergistic Mechanism and Potential Application of Immune Checkpoint Blockade Combined With Lenvatinib

“…The combined use of lenvatinib and ICB to promote CD8 + T cell infiltration and inhibit the number and function of Tregs, M2 macrophages, or MDSCs (in terms of IL10 or TGF-β secretion) has been confirmed in murine models of LIHC (Kimura et al, 2018;Kudo, 2019), COAD (Kato et al, 2019), and THCA (Gunda et al, 2019). Lenvatinib can also reduce tumor PD-L1 level to improve anti-PD-1 efficacy by blocking FGFR4 (Yi et al, 2021). The mechanisms of action of lenvatinib include (Figure 6): downregulating the expression of PD-1, CTLA-4, and TIM3 in T cells; blocking the binding of VEGFA and bFGF to their receptors, thereby inhibiting T-cell exhaustion (Deng et al, 2020); and destroying tumor cells, leading to the release of tumor antigens, which in turn promotes IFN-γ-mediated antigen presentation (Kato et al, 2019) and enhances the cytotoxicity of natural killer cells (Zhang et al, 2019).…”

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

“…Previous studies also indicated that lenvatinib could strongly inhibit the activation of ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib [ 32 ], and high FGFR4 levels (positive immunohistochemistry >10% of tumor cells) were an independent predictor of a response to lenvatinib [ 33 ]. Moreover, lenvatinib enhanced the antitumor immune response of anti-programmed cell death-1 (PD-1) in HCC by blocking FGFR4 [ 34 ]. However, lenvatinib alone could inhibit HCC cancer stem-like cells through FGFR1-3 signaling, but not FGFR4 signaling [ 35 ].…”

Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

“…LEN significantly decreased the population of tumor-associated macrophages, as well as increased the percentage of activated CD8+ T cells secreting interferon-γ+ and granzyme B ( 24 , 25 ). In addition, LEN significantly reduced the level of tumor programmed death-ligand 1 (PD-L1) and Treg differentiation, improved anti-PD-1 efficacy by blocking FGFR4, and inhibiting TGFß signaling ( 26 , 27 ). The extent to which combination therapies pose clinical safety and tolerability challenges, and whether these challenges will limit their usefulness as an anticancer therapy, have been the focus of an increasing number of studies.…”