Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model

作者：Takayuki Kimura, Yu Kato, Yoichi Ozawa, Kotaro Kodama, Jun‐ichi Ito, Kenji Ichikawa, Kazuhiko Yamada, Yusaku Hori, Kimiyo Tabata, Kazuma Takase, Junji Matsui, Yasuhiro Funahashi, K. Nomoto · 发表于：Cancer Science · 年份：2018 · DOI：10.1111/cas.13806 · 被引用次数：349 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Cancer Mechanisms and Therapy、Cancer Immunotherapy and Biomarkers

Abstract 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 ICI s 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 CD 8 + 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 macro...