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.

Department of Animal Physiology and Immunology Institute of Experimental Biology Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy

Department of Experimental Biomedicine and Clinical Neurosciences University of Palermo Palermo Italy

Department of Histopathology Royal Free London NHS Foundation Trust London United Kingdom

Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic

International Clinical Research Center St' Anne's University Hospital Brno Czech Republic

IRCCS Casa Sollievo della Sofferenza Laboratory of Bioinformatics San Giovanni Rotondo Italy

Translational Cell and Tissue Research Unit Department of Imaging and Pathology Katholieke Universiteit Leuven Leuven Belgium

UCL Institute for Liver and Digestive Health Royal Free Hospital London United Kingdom

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