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Study of the fate of resident macrophages and monocytes upon partial liver resection and their impact on hepatocarcinoma outgrowth

par Hastir, Jean-Francois
Président du jury Le Moine, Alain
Promoteur Flamand, Véronique
Publication Non publié, 2020-06-25

Thèse de doctorat

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Résumé :

Partial hepatectomy (PH) is a treatment of choice for patients suffering from early stage hepatocellular carcinoma (HCC). Ablation of large proportion of the liver is rendered possible because of the ability of the liver to regenerate. Yet, a significant number of patients will experience recursion of the disease. Such relapses are unfortunately rather frequent and constitute a bad prognosis. The development of new strategies aiming at reducing the risk of recursion of HCC is thus a paramount element of the surgery-based treatment. Some previous studies have proposed that the regenerative process as well as the fate of the immune cells during the liver regeneration process is linked to this recurrence phenomenon.In this study, we investigated the impact of PH on HCC development in a pre-clinical murine model. We implanted Hepa1-6 hepatocarcinoma cells (a murine hepatocarcinoma cell line) directly in the liver of mice and compared a non-resected group with a group undergoing 40% PH one week following tumor implantation. Analysis were relying on bioluminescence imaging and flow cytometry. We demonstrated that liver regeneration increases tumoral proliferation. This proliferation was associated with a reduction in the number of liver resident macrophages, i.e. Kupffer cells (KC). KC anti-tumoral activity was also proved using conditional ablation model. We further studied the mechanisms leading to this disappearance and demonstrated that, under normal regeneration conditions, PH-induced KC number reduction was dependent on tumor necrosis factor-α (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 Hepa 1-6 encounter, the KC reduction changed toward a TNF-α-RIPK3-caspase-1 activation. This data suggest a switch from apoptosis to pyroptosis induction in KC following PH. 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, underlying the importance of macrophages activated death-pathway in regulating the anti-tumoral immune response. Our results show the necessity for comprehensive multidisciplinary treatment approach following PH and propose new targets in order to reduce the relapse of the disease occurring after surgery.