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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Abstract

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
Volume10
DOIs
Publication statusPublished - 16 Oct 2020

Bibliographical note

Funding Information:
This study was supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium), the FNRS-Télévie grant, the Rose et Jean Hoguet foundation, the Fonds Erasme, the Fonds pour la recherche médicale dans le Hainaut (FRMH), and the Walloon Region (FEDER Wallonia-Biomed portfolio).

Funding Information:
We thank Arnaud K?hler for handling/breeding genetically modified mice, Clara Valentin for intracellular staining, Fr?d?ric Paulart for scientific expertise, and Philippe Horlait, Laurent Depret, Christophe Notte, Gr?gory Waterlot, and Samuel Vanderbiest for animal care. Funding. This study was supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium), the FNRS-T?l?vie grant, the Rose et Jean Hoguet foundation, the Fonds Erasme, the Fonds pour la recherche m?dicale dans le Hainaut (FRMH), and the Walloon Region (FEDER Wallonia-Biomed portfolio).

Publisher Copyright:
© Copyright © 2020 Hastir, Delbauve, Larbanoix, Germanova, Goyvaerts, Allard, Laurent, Breckpot, Beschin, Guilliams and Flamand.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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