Hepatocarcinoma induces a tumor necrosis factor-dependent Kupffer cell death pathway that favors its proliferation upon partial hepatectomy

Jean-Francois Hastir, Sandrine Delbauve, Lionel Larbanoix, Desislava Germanova, Cleo Goyvaerts, Justine Allard, Sophie Laurent, Karine Breckpot, Alain Beschin, Martin Guilliams, Véronique Flamand

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Partial hepatectomy (PH) is the main treatment for early-stage hepatocellular carcinoma(HCC). Yet, a significant number of patients undergo recursion of the disease that couldbe linked to the fate of innate immune cells during the liver regeneration process. In thisstudy, using a murine model, we investigated the impact of PHon HCC developmentby bioluminescence imaging and flow cytometry. While non-resected mice were able tocontrol and reject orthotopic implanted Hepa1-6 hepatocarcinoma cells, resected liverunderwent an increased tumoral proliferation. This phenomenon was associated with aPH-induced reduction in the number of liver-resident macrophages, i.e., Kupffer cells(KC). Using a conditional ablation model, KC were proved to participate in Hepa1-6rejection. We demonstrated that in the absence of Hepa1-6, PH-induced KC numberreduction was dependent on tumor necrosis factor-alpha (TNF-α), receptor-interactingprotein kinase (RIPK) 3, and caspase-8 activation, whereasinterleukin (IL)-6 acted asa KC pro-survival signal. In mice with previous Hepa1-6 encounter, the KC reductionswitched toward a TNF-α-RIPK3–caspase-1 activation. Moreover, KC disappearanceassociated with caspase-1 activity induced the recruitment of monocyte-derived cellsthat are beneficial for tumor growth, while caspase-8-dependent reduction did not. Inconclusion, our study highlights the importance of the TNF-α-dependent death pathwayinduced in liver macrophages following partial hepatectomy in regulating the antitumoralimmune responses.
Original languageEnglish
Article number547013
JournalFrontiers in Oncology
Publication statusPublished - 16 Oct 2020

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