Vessels encapsulating tumor clusters promote non-invasive metastasis of hepatocellular carcinoma by shaping an immunosuppressive microenvironment

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Abstract

Vessels encapsulating tumor clusters (VETC), a distinct vascular pattern in hepatocellular carcinoma (HCC), facilitates non-invasive metastasis in whole cluster. The interaction between VETC and tumor microenvironment requires exploration. Here, we found that compared to human Non-VETC-HCCs, VETC-tumors exhibited more PD1+CD8+ T cells and Tregs, especially TNFRSF4+Tregs and Ki67+Tregs which showed increased immunosuppressive and proliferative activity. Such immunosuppressive status was also detected in tumor emboli of VETC-HCCs, and Treg density in emboli was positively associated with metastatic cell proliferation. VETC-HCCs revealed abundance correlation, closer spatial proximity, and stronger immunosuppressive ligand-receptor interactions between TNFRSF4+Tregs/Ki67+Tregs and PD1+CD8+ T cells. Depleting Tregs in mice reduced PD1+CD8+ T cells in primary lesions, tumor emboli and metastatic foci of VETC-allografts, and attenuated allograft metastasis. TGF-β1 levels were upregulated in endothelial cells of VETC-HCCs and associated with TNFRSF4+Tregs/Ki67+Tregs enrichment. Disrupting VETC formation decreased endothelial TGF-β1 expression, and reduced TNFRSF4+Tregs/Ki67+Tregs, PD1+CD8+ T cells, Treg/CD8+ T cells ratio. Collectively, VETC may enhance Tregs’ activity via TGF-β1, while Tregs promote and sustain CD8+ T cell exhaustion through immune inhibitory ligand-receptor interaction, thereby shaping immunosuppressive microenvironment and enabling tumor cluster to carry such niche to disseminate. These findings disclose mechanisms of tumor immune microenvironment formation and provide rationales for precision medicine.

Authors

Bi-Yu Huang, Zheng-Qi Mi, Xiao-Yu Zhang, Yu-Chen Ji, Meng-Zhi Wu, Zi-Feng Cheng, Chen Xie, Shuai He, Jing Zhu, Jian-Hong Fang, Chong Wu, Bin-Kui Li, Yun-Fei YUAN, Limin Zheng, Shi-Mei Zhuang