Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8
+
T cells secreting interferon (IFN)-γ
+
and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8
+
T cells, among CD45
+
cells and increased IFN-γ
+
and GzmB
+
CD8
+
T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.
Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐4, platelet‐derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti‐programmed cell death 1 (PD‐1) antibody in the Hepa1‐6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti‐PD‐1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single‐cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti‐PD‐1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti‐PD‐1 antibody. Combination treatment of lenvatinib plus anti‐PD‐1 antibody therefore warrants further investigation against advanced HCC.
Merging cooperative Si-H bond activation and electrophilic aromatic substitution paves the way for C-3-selective indole C-H functionalization under electronic and not conventional steric control. The Si-H bond is heterolytically split by the Ru-S bond of a coordinatively unsaturated cationic ruthenium(II) complex, forming a sulfur-stabilized silicon electrophile. The Wheland intermediate of the subsequent Friedel-Crafts-type process is assumed to be deprotonated by the sulfur atom, no added base required. The overall catalysis proceeds without solvent at low temperature, only liberating dihydrogen.
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