Theranostics 2020; 10(2):910-924. doi:10.7150/thno.35045 This issue

Research Paper

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Oriana Lo Re1,2*, Tommaso Mazza3*, Sebastiano Giallongo1,2, Paola Sanna1, Francesca Rappa4, Tu Vinh Luong5, Giovanni Li Volti6, Adela Drovakova7,8, Tania Roskams9, Matthias Van Haele9, Emmanuel Tsochatzis10, Manlio Vinciguerra1,10✉

1. International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic;
2. Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic;
3. IRCCS Casa Sollievo della Sofferenza, Laboratory of Bioinformatics, San Giovanni Rotondo (FG), Italy;
4. Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy;
5. Department of Histopathology, Royal Free London NHS Foundation Trust, London, United Kingdom;
6. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy;
7. Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic;
8. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic;
9. Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, Katholieke Universiteit Leuven, Leuven, Belgium;
10. UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom.
*these authors contributed equally

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Lo Re O, Mazza T, Giallongo S, Sanna P, Rappa F, Vinh Luong T, Li Volti G, Drovakova A, Roskams T, Van Haele M, Tsochatzis E, Vinciguerra M. Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation. Theranostics 2020; 10(2):910-924. doi:10.7150/thno.35045. Available from

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Graphic abstract

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear.

Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses.

Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs).

Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance.

Keywords: hepatocellular carcinoma, histone macroH2A1, adaptive immune system, chemoresistance.