Résumé
Simple Summary Despite all of the advancements made in recent years in the treatment of acute myeloid leukemia (AML), long-term survival is achieved by only 30-40% of AML patients. Thus, new therapeutic strategies are strongly needed. This work confirms the increase in oxidative phosphorylation upon cytarabine resistance in AML murine cells, reinforcing the interest of targeting it. In addition, it identifies a new role of the first complex of the electron transport chain (ETCI) in the regulation of the immune checkpoints PD-L1 and CD39 in murine and human leukemic cells. Thus, this work opens the door to the evaluation of ETCI inhibitors in combination with immunotherapy. Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve the therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as ectonucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemo-resistance and a poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased the OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that while AraC induced an immune response regulation by increasing CD39 expression and by reinforcing the interferon-gamma/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML.