Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression
Peng Sun,
Zhenfeng Li,
Zaojun Yan,
Zhaofeng Wang,
Peng Zheng,
Mingliang Wang,
Xu Chang,
Zihao Liu,
Jianxin Zhang,
Huiyong Wu,
Wenbo Shao,
Dewen Xue,
Jinming Yu
Affiliations
Peng Sun
National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University, Tianjin Medical University Cancer Institute and Hospital
Zhenfeng Li
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Zaojun Yan
Department of Infection, The People’s Hospital of Rizhao
Zhaofeng Wang
Surgical Department, Jinan Jiyang District Hospital of Traditional Chinese Medicine
Peng Zheng
Oncology Department, The People’s Hospital of Xiajin
Mingliang Wang
Oncology Department, The People’s Hospital of Xiajin
Xu Chang
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Zihao Liu
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Jianxin Zhang
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Huiyong Wu
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Wenbo Shao
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Dewen Xue
Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
Jinming Yu
National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University, Tianjin Medical University Cancer Institute and Hospital
Abstract Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.
