Myeloid tumor necrosis factor and heme oxygenase‐1 regulate the progression of colorectal liver metastases during hepatic ischemia‐reperfusion

The liver ischemia‐reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor‐interating protein 3 kinase (RIPK3) and caspase‐1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor‐α (TNF‐α) and heme oxygenase‐1 (HO‐1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNFflox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell‐derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor‐β, interleukin (IL)‐10, inducible nitric oxyde synthase (iNOS), IL‐33 and HO‐1. Conversely, a monocyte/macrophage‐specific deficiency in HO‐1 (HO‐1flox/flox LysMcre/wt) or the blockade of HO‐1 function led to the control of tumor progression post‐liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR‐induced innate cell recruitment, increases the TNF level, decreases the HO‐1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO‐1 inhibition would reinforce their antitumoral activity. What's new? Liver ischemia/reperfusion during surgical procedures such as partial hepatectomy contributes to colorectal liver metastasis progression. The underlying mechanisms are only partially understood. Here, using a mouse model of colorectal liver metastasis, the authors reveal that metastasis progression is correlated with the local production of TNF and HO‐1 by resident Kupffer cells and recruited monocytes. Liver ischemia/reperfusion leads to a decrease in Kupffer cells, most likely through inflammatory cell death induction, that favours the recruitment of TNF‐producing protective monocytes. The findings further sug