Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8+T cell infiltration

癌症研究 CD8型 肿瘤微环境 细胞毒性T细胞 T细胞 渗透(HVAC) 抗体 医学 免疫系统 化学 免疫学 体外 生物化学 热力学 物理 肿瘤细胞
作者
Lunbiao Gan,Tong Lü,Yu Lu,Hongtao Song,Jiayu Zhang,Keying Zhang,Shi-Qi Lu,Xinjie Wu,Fei Nie,Shin Di,Donghui Han,Fa Yang,Weijun Qin,Weihong Wen
出处
期刊:Journal for ImmunoTherapy of Cancer [BMJ]
卷期号:12 (9): e009111-e009111
标识
DOI:10.1136/jitc-2024-009111
摘要

Background and aims Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. Approach and results The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (EN KO ) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from EN KO mice had increased CD8 + T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8 + T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8 + T cell infiltration. High level of endosialin protein expression was correlated with low CD8 + T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. Conclusions Endosialin could inhibit CD8 + T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.
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