In hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV+ HCC), the mechanisms by virus-derived antigens shape the T cell immune response remains unclear. Here, we employed bulk and single-cell multi-omics sequencing technologies to study the T cell receptor (TCR) repertoire, antigen specificity and epigenomic profiles in HBV+ HCC patients. We found that HBV is a major driver of T cells, with HBV-specific recurrent and expanding TCR clonotypes from CD8+ T cells, mucosal-associated invariant T (MAIT) cells and regulatory T cells (Tregs). HBV virions can directly activate MAIT cells in a MR1-dependent manner, indicating that these cells are not only sensors of metabolic products, but could participate directly in pathogen defense. And increased numbers of intratumoral Tregs, many of which are HBV specific, correlated with both increased viral titers and tumor size, while more a robust expansion of virus specific CD8+ T cells had better clinical prognosis after surgery. Integrating TCR and ATAC sequences also allowed us to track the epigenomic changes of specific T cell clonal lineages, with HBV-specific conventional CD8+ T cells expressing an effector phenotype when adjacent to the tumor, but cells of the same lineage exhibiting an “exhausted” phenotype in the tumor itself.
Chen, Liang and You, Maojun and Tian, Meijie and Fu, Junliang and Gao, Yanan and Wang, Chunlin and Mu, Zepeng and Li, Yang I. and Wang, Feng and Teng, Xueyi and Zhu, Zhenyu and Hong, Zhixian and Liang, Jie and Chen, Runsheng and Wang, Fu-Sheng and Yang, Pengyuan and Davis, Mark M., Hepatitis B Virus Drives Divergent Adaptive Immunity in Hepatocellular Carcinoma. Available at SSRN: https://ssrn.com/abstract=3720764 or http://dx.doi.org/10.2139/ssrn.3720764
This version of the paper has not been formally peer reviewed.
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