中国病理生理杂志2024，Vol.40Issue(5)：786-795,10.DOI:10.3969/j.issn.1000-4718.2024.05.003
仑伐替尼通过调节肿瘤免疫微环境协同增强免疫检查点抑制剂对肝细胞癌的疗效
Lenvatinib modulates tumor immune microenvironment to synergistical-ly enhance immune checkpoint inhibitor treatment of hepatocellular car-cinoma
摘要
Abstract
AIM:To explore the efficacy of lenvatinib(Len)in enhancing the therapeutic effects of immune checkpoint inhibitor for hepatocellular carcinoma(HCC)and to delve into its immunomodulatory mechanisms within the tumor microenvironment.METHODS:The effects of various concentrations of Len on the migration of human umbilical vein endothelial cells(HUVECs)and the secretion of CXC chemokine ligand 10(CXCL10)were investigated,and the mechanism by which Len modulates CXCL10 secretion was validated.An orthotopic HCC model was established,and the mice bearing tumors were randomly allocated into 4 groups:PBS group,BMS-202(PD-1/PD-L1 inhibitor)group,Len group,and Len/BMS-202 group.The progression of the orthotopic liver tumors was monitored with small animal in vivo im-aging techniques.On the 13th day after the treatment,mice were sacrificed and tumor tissues were harvested for analysis.Immunofluorescence was employed to identify apoptosis,vascular architecture,and hypoxic status within the tumor tis-sue.The expression levels of proliferation marker Ki67,transforming growth factor-β(TGF-β),and the infiltration de-grees of CD4+T cells and CD8+T cells in the tumor tissue were monitored with immunohistochemistry.The secretion of im-mune factors interferon-γ(IFN-γ),CXCL10 and TGF-α in the mouse serum was quantified with ELISA.Above all data were followed by statistical analysis.RESULTS:(1)Len could facilitate endothelial cell migration within a specific range and potentiated the response of tumor cells to IFN-γ by blocking fibroblast growth factor receptor(FGFR),thereby increasing the secretion of CXCL10 from the tumor cells.(2)Compared with PBS group,tumor growth was slower in all treatment groups,with Len/BMS-202 group showing the most significant inhibition of tumor growth in tumor-bearing mice(P<0.05).(3)Compared with PBS group and monotherapy groups,Len/BMS-202 significantly promoted tumor tissue apoptosis and inhibited tumor cell proliferation(P<0.05).(4)Compared with PBS group and BMS-202 group,both Len group and Len/BMS-202 group manifested a substantial enhancement in pericytes coverage rate(P<0.01),concomitantly showing a marked improvement in hypoxic conditions(P<0.01).(5)Compared with PBS group and monotherapy groups,Len/BMS-202 group showed a significant increase in the infiltration of CD4+T cells and CD8+T cells within the tumor(P<0.01),along with a marked decrease in the expression of TGF-β(P<0.01).(6)Compared with PBS group,all treatment groups collectively induced varying degrees of secretion of IFN-γ,CXCL10 and TGF-α in mouse serum(P<0.05),with Len/BMS-202 group demonstrating the most pronounced effects(P<0.01).CONCLUSION:Lenvatinib may augment the therapeutic efficacy of BMS-202 in HCC by facilitating tumor vascular normalization,alleviating hypoxic conditions,and enhancing the secretion of CXCL10,thereby synergistically activating the tumor immune microenvironment.关键词
免疫调节/肿瘤微环境/仑伐替尼/免疫检查点抑制剂/肝细胞癌Key words
immunomodulation/tumor microenvironment/lenvatinib/immune checkpoint inhibitor/hepato-cellular carcinoma分类
医药卫生引用本文复制引用
李嘉敏,杨蕊梦,韦瑞丽,姚旺,张婉丽,江新青..仑伐替尼通过调节肿瘤免疫微环境协同增强免疫检查点抑制剂对肝细胞癌的疗效[J].中国病理生理杂志,2024,40(5):786-795,10.基金项目
国家自然科学基金资助项目(No.82271938 （）
No.82371908 （）
No.81971574) （）
广东省基础与应用基础研究基金企业联合基金(省企联合基金)-面上项目(No.2021A1515220060) （省企联合基金）
广州市重点实验室建设项目(No.202201020376) （No.202201020376）
