Frontiers in Immunology (Jul 2023)

Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRβ complex in hepatocellular carcinoma

  • Jieying Yang,
  • Jieying Yang,
  • Zhixing Guo,
  • Zhixing Guo,
  • Mengjia Song,
  • Mengjia Song,
  • Qiuzhong Pan,
  • Qiuzhong Pan,
  • Jingjing Zhao,
  • Jingjing Zhao,
  • Yue Huang,
  • Yulong Han,
  • Dijun Ouyang,
  • Dijun Ouyang,
  • Chaopin Yang,
  • Chaopin Yang,
  • Hao Chen,
  • Hao Chen,
  • Muping Di,
  • Muping Di,
  • Yan Tang,
  • Yan Tang,
  • Qian Zhu,
  • Qijing Wang,
  • Qijing Wang,
  • Yongqiang Li,
  • Yongqiang Li,
  • Jia He,
  • Jia He,
  • Desheng Weng,
  • Desheng Weng,
  • Tong Xiang,
  • Tong Xiang,
  • JianChuan Xia,
  • JianChuan Xia

DOI
https://doi.org/10.3389/fimmu.2023.1212577
Journal volume & issue
Vol. 14

Abstract

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IntroductionThe limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms.MethodsThe effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging.ResultsThere was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRβ complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth.ConclusionsOur study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

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