Hepatology, 1 September, 2023, DOI：https://doi.org/10.1097/HEP.0000000000000369

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC

You, Maojun; Gao, Yanan; Fu, Junliang; Xie, Runze; Zhu, Zhenyu; Hong, Zhixian; Meng, Lingzhan; Du, Shunda; Liu, Junliang; Wang, Fu-Sheng; Yang, Pengyuan; Chen, Liang

Abstract

Background and Aims:

HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear.

Approach and Results:

We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αβ T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients.

Conclusions:

This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.

Article link：https://journals.lww.com/hep/fulltext/2023/09000/epigenetic_regulation_of_hbv_specific.23.aspx