Multimodal epigenomic landscape of tumor infiltrating T cells reveals virus-driving divergent adaptive immunity in HBV-related hepatocellular carcinoma

Hepatitis B virus (HBV) infection is the most prevalent etiological factor for hepatocellular carcinoma (HCC). However, whether or how HBV-derived antigens shape the T cell immune responses remains largely unknown. Here, we comprehensively investigated the accessible chromatin, T cell receptor (TCR) repertoire and antigen specificity of tumor-infiltrating T cells (TILs) in HBV-related HCC (HBV+ HCC) via bulk and single-cell multi-omics sequencing. We found that even in the presence of the carcinoma, HBV is a major driver of T cells in HBV+ HCC, with enhanced TCR-mediated NFKB and NR4A1 signal activation. Interestingly, more than 1/3 of the expanding TCR clonotypes from HBV+ HCC were specific for HBV-derived antigens. Integrating TCR antigen specificity and accessible chromatin also allowed us to track the epigenomic changes of specific TIL clonal lineages, with HBV-specific 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. However, the increased numbers of tumor-infiltrating Tregs, many of which were HBV specific, correlated with both increased viral titers and tumor size, suggesting that greater suppression of effector T cells enhances HBV-associated tumor growth. Therefore, our multimodal epigenomic profiles of HBV+ HCC infiltrating T cells show a variety of virus-specific cells and HBV antigens driving adaptive immune divergency, indicative of implications for new targets of cancer immunotherapy of HCC.