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INTRODUCTION

The 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.

METHODS

The 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.

RESULTS

There 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.

CONCLUSIONS

Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

INTRODUCTION

METHODS

RESULTS

CONCLUSIONS

Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

简介

免疫检查点阻断（ICBs）在肝细胞癌（HCC）患者中的有限反应突显了拓宽当前免疫治疗方法范围的迫切需要。仑伐替尼已显示出与 ICBs 的潜在协同作用。本研究探讨了联合这两种治疗药物的最佳方法及其潜在机制。

方法

在免疫缺陷和免疫功能正常的小鼠模型中，评估了仑伐替尼三种不同剂量对促进组织灌注和血管正常化的影响。通过分析内皮细胞和周细胞的血管形态，研究了潜在机制。通过流式细胞术和免疫荧光成像进一步评估了最佳剂量仑伐替尼的增强免疫浸润及其与抗 PD-1 抗体的协同作用。

结果

在免疫缺陷和免疫功能正常的小鼠模型中，存在一个最佳剂量，可更好地使肿瘤血管正常化并增加免疫细胞浸润。仑伐替尼的适当浓度通过诱导 NRP-1-PDGFRβ 复合物的形成并激活内皮细胞中的 Crkl-C3G-Rap1 信号通路，增强了人脐静脉内皮细胞的完整性。此外，它通过诱导周细胞中的酪氨酸磷酸化，促进了内皮细胞与周细胞之间的相互作用。此外，最佳剂量的仑伐替尼与抗 PD-1 抗体的联合强烈抑制了肿瘤生长。