Integrative Epigenetic Analysis Reveals AP-1 Promotes Activation of Tumor-infiltrating Regulatory T Cells in HCC

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2023 Mar 21

PMID 36941472

Authors

Baowen Zhuo

Qifan Zhang

Tingyan Xie

Yidan Wang

Zhengliang Chen

Daming Zuo

Bo Guo

Affiliations

Soon will be listed here.

Abstract

Regulatory T (Treg) cells that infiltrate human tumors exhibit stronger immunosuppressive activity compared to peripheral blood Treg cells (PBTRs), thus hindering the induction of effective antitumor immunity. Previous transcriptome studies have identified a set of genes that are conserved in tumor-infiltrating Treg cells (TITRs). However, epigenetic profiles of TITRs have not yet been completely deciphered. Here, we employed ATAC-seq and CUT&Tag assays to integrate transcriptome profiles and identify functional regulatory elements in TITRs. We observed a global difference in chromatin accessibility and enhancer landscapes between TITRs and PBTRs. We identified two types of active enhancer formation in TITRs. The H3K4me1-predetermined enhancers are poised to be activated in response to tumor microenvironmental stimuli. We found that AP-1 family motifs are enriched at the enhancer regions of TITRs. Finally, we validated that c-Jun binds at regulatory regions to regulate signature genes of TITRs and AP-1 is required for Treg cells activation in vitro. High c-Jun expression is correlated with poor survival in human HCC. Overall, our results provide insights into the mechanism of AP-1-mediated activation of TITRs and can hopefully be used to develop new therapeutic strategies targeting TITRs in liver cancer treatment.

Citing Articles

Advances in the relationship between AP-1 and tumorigenesis, development and therapy resistance.

Xue X, Li Z, Zhao J, Zhao Z, Li Z, Li Y Discov Oncol. 2025; 16(1):61.

PMID: 39831917 PMC: 11747019. DOI: 10.1007/s12672-025-01783-1.

Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.

Chen Y, Liang R, Li Y, Jiang L, Ma D, Luo Q Signal Transduct Target Ther. 2024; 9(1):340.

PMID: 39627201 PMC: 11615378. DOI: 10.1038/s41392-024-02030-9.

References

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

Tanaka A, Sakaguchi S . Regulatory T cells in cancer immunotherapy. Cell Res. 2016; 27(1):109-118. PMC: 5223231. DOI: 10.1038/cr.2016.151. View

Zhuo B, Yu J, Chang L, Lei J, Wen Z, Liu C . Quantitative analysis of chromatin accessibility in mouse embryonic fibroblasts. Biochem Biophys Res Commun. 2017; 493(1):814-820. DOI: 10.1016/j.bbrc.2017.08.065. View

Klemm S, Shipony Z, Greenleaf W . Chromatin accessibility and the regulatory epigenome. Nat Rev Genet. 2019; 20(4):207-220. DOI: 10.1038/s41576-018-0089-8. View

Guo X, Zhang Y, Zheng L, Zheng C, Song J, Zhang Q . Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018; 24(7):978-985. DOI: 10.1038/s41591-018-0045-3. View

Zheng C, Zheng L, Yoo J, Guo H, Zhang Y, Guo X . Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell. 2017; 169(7):1342-1356.e16. DOI: 10.1016/j.cell.2017.05.035. View

Wing J, Tanaka A, Sakaguchi S . Human FOXP3 Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer. Immunity. 2019; 50(2):302-316. DOI: 10.1016/j.immuni.2019.01.020. View

Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

Lau C, Adams N, Geary C, Weizman O, Rapp M, Pritykin Y . Epigenetic control of innate and adaptive immune memory. Nat Immunol. 2018; 19(9):963-972. PMC: 6225771. DOI: 10.1038/s41590-018-0176-1. View

10.

Yang X, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H . Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol. 2006; 45(2):254-62. DOI: 10.1016/j.jhep.2006.01.036. View

11.

Li Z, Schulz M, Look T, Begemann M, Zenke M, Costa I . Identification of transcription factor binding sites using ATAC-seq. Genome Biol. 2019; 20(1):45. PMC: 6391789. DOI: 10.1186/s13059-019-1642-2. View

12.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

13.

Shimizu J, Yamazaki S, Sakaguchi S . Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999; 163(10):5211-8. View

14.

Schmidl C, Hansmann L, Lassmann T, Balwierz P, Kawaji H, Itoh M . The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood. 2014; 123(17):e68-78. DOI: 10.1182/blood-2013-02-486944. View

15.

Polansky J, Schreiber L, Thelemann C, Ludwig L, Kruger M, Baumgrass R . Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med (Berl). 2010; 88(10):1029-40. PMC: 2943068. DOI: 10.1007/s00109-010-0642-1. View

16.

Ohkura N, Yasumizu Y, Kitagawa Y, Tanaka A, Nakamura Y, Motooka D . Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases. Immunity. 2020; 52(6):1119-1132.e4. DOI: 10.1016/j.immuni.2020.04.006. View

17.

Forner A, Reig M, Bruix J . Hepatocellular carcinoma. Lancet. 2018; 391(10127):1301-1314. DOI: 10.1016/S0140-6736(18)30010-2. View

18.

Azizi E, Carr A, Plitas G, Cornish A, Konopacki C, Prabhakaran S . Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell. 2018; 174(5):1293-1308.e36. PMC: 6348010. DOI: 10.1016/j.cell.2018.05.060. View

19.

Smale S, Fisher A . Chromatin structure and gene regulation in the immune system. Annu Rev Immunol. 2002; 20:427-62. DOI: 10.1146/annurev.immunol.20.100301.064739. View

20.

Vargas F, Furness A, Litchfield K, Joshi K, Rosenthal R, Ghorani E . Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer Cell. 2018; 33(4):649-663.e4. PMC: 5904288. DOI: 10.1016/j.ccell.2018.02.010. View