Macrophage autophagy protects against hepatocellular carcinogenesis in mice


Deust A, Chobert M-N, Demontant V, Gricourt G, Denaës T, Thiolat A, Ruiz I, Rodriguez C, Pawlotsky JM & Teixeira-Clerc F. Contact:Fatima Teixeira-Clerc – CR Inserm –

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Scientific Reports


Macrophage autophagy protects against hepatocellular carcinoma by regulating the immune microenvironment Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. HCC typically develops on a background of chronic inflammation with macrophages playing an important role in this process. In this work, the authors observed that liver cancer cells inhibit autophagy in macrophages, a mechanism that is involved in the regulation of the immune responses. To investigate the consequences of macrophage autophagy inhibition on hepatocarcinogenesis, the authors exposed mice invalidated for macrophage autophagy (ATG5Mye-/- mice) to a model of hepatic carcinogenesis induced by administration of diethylnitrosamine (DEN). DEN-treated ATG5Mye-/- mice show enhanced tumor development compared to wild type mice. Characterization of the hepatic immune cell populations demonstrate that DEN-treated ATG5Mye-/- mice show a decrease in the number and the activation of hepatic macrophages and T cells. Moreover, a transcriptomic analysis using next generation sequencing shows that the hepatic macrophages isolated from DEN-treated ATG5Mye-/- mice exhibit a more immunosuppressive phenotype than the macrophages isolated from wild type mice. In addition, the authors show for the first time that autophagy regulates the expression of the co-inhibitory immune checkpoint molecule PD-L1 by macrophages: activation of autophagy reduces the expression of PD-L1 induced by tumor cells while inhibition of autophagy increases the expression of PD-L1. These results suggest the existence of a vicious circle in which tumor cells alter the tumor microenvironment by inhibiting macrophage autophagy leading to the overexpression of PD-L1, which, in turn, will promote tumor growth by inducing an immunosuppressive microenvironment.

Graphical abstract

Macrophage autophagy protects against hepatocellular carcinogenesis in mice