Hepatocarcinoma Induces a Tumor Necrosis Factor-Dependent Kupffer Cell Death Pathway That Favors Its Proliferation Upon Partial Hepatectomy

Frontiers in Oncology

Sophie Laurent¹  Lionel Larbanoix¹  Martin Guilliams²  Justine Allard³  Véronique Flamand⁴  Jean-François Hastir⁴  Desislava Germanova⁴  Sandrine Delbauve⁴  Karine Breckpot⁵  Cleo Goyvaerts⁵  Alain Beschin⁸ 

[1] Center for Microscopy and Molecular Imaging, Université de Mons, Brussels, Belgium;Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium;Diapath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Brussels, Belgium;Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium;Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium;Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium;Myeloid Cell Immunology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium;

关键词: Kupffer cells;    hepatocellular carcinoma;    liver regeneration;    partial hepatectomy;    cell death;    inflammation;   

DOI  :  10.3389/fonc.2020.547013

来源: DOAJ

【 摘 要 】

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 could be linked to the fate of innate immune cells during the liver regeneration process. In this study, using a murine model, we investigated the impact of PH on HCC development by bioluminescence imaging and flow cytometry. While non-resected mice were able to control and reject orthotopic implanted Hepa1-6 hepatocarcinoma cells, resected liver underwent an increased tumoral proliferation. This phenomenon was associated with a PH-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 Hepa1-6 rejection. We demonstrated that in the absence of Hepa1-6, PH-induced KC number reduction was dependent on tumor necrosis factor-alpha (TNF-α), receptor-interacting protein kinase (RIPK) 3, and caspase-8 activation, whereas interleukin (IL)-6 acted as a KC pro-survival signal. In mice with previous Hepa1-6 encounter, the KC reduction switched toward a TNF-α-RIPK3–caspase-1 activation. Moreover, KC disappearance associated with caspase-1 activity induced the recruitment of monocyte-derived cells that are beneficial for tumor growth, while caspase-8-dependent reduction did not. In conclusion, our study highlights the importance of the TNF-α-dependent death pathway induced in liver macrophages following partial hepatectomy in regulating the antitumoral immune responses.

【 授权许可】

Unknown