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Epigenetic modulation of immunity: towards new therapeutic avenues in hepatocellular carcinoma?
  1. Angelique Gougelet
  1. Correspondence to Dr Angelique Gougelet, UMRS1138-Team 24, Centre de Recherche des Cordeliers, Paris 75006, France; angelique.gougelet{at}inserm.fr

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Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeutic options are very limited and novel strategies alarmingly needed. The leading risk factor for hepatocellular carcinoma (HCC) is cirrhosis due to HBV and HCV viruses, alcohol abuse, genotoxic exposure and metabolic disorders increasingly associated with diabetes and obesity. HCC is the paradigm of inflammation-associated cancer, with >80% of HCC emerging consecutively to a vast remodelling of liver stroma. To restrain inflammatory response, liver parenchyma physiologically harbours a specific microenvironment to prevent the establishment of inflammation. Immune cells largely orchestrate liver protection, in particular Kupffer cells, the liver macrophages, in partnership with fibroblasts. Nevertheless, when it gets into chronicity, liver inflammation sensitises to cancer development, tumor-associated stroma being recognised as a major hallmark of cancer, as described by Hanahan and Weinberg in 2011.1 During hepatocyte transformation, the surrounding cells, including cancer-associated fibroblasts, hepatic stellate cells, tumour-infiltrating leukocytes and tumour-associated macrophages (TAM) are abnormally activated and/or recruited. These cells secrete a cocktail of growth factors, cytokines and chemokines, which exacerbate liver inflammation and injury in favour of hepatocarcinogenesis.2 Macrophages are the major part of immune cell infiltrates in solid tumours, and the density of macrophages is strongly correlated to poor overall survival, including in HCC. Inversely, myeloid-derived suppressor cells (MDSCs) have emerged as central …

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