PMID- 34298712 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210729 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 13 IP - 14 DP - 2021 Jul 13 TI - Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells. LID - 10.3390/cancers13143499 [doi] LID - 3499 AB - 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. FAU - Luna-Yolba, Raquel AU - Luna-Yolba R AUID- ORCID: 0000-0003-1315-858X AD - EVOTEC, Campus Curie, 31100 Toulouse, France. AD - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, Inserm, CNRS, 31100 Toulouse, France. AD - LabEx Toucan, 31100 Toulouse, France. AD - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, 31100 Toulouse, France. FAU - Marmoiton, Justine AU - Marmoiton J AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Gigo, Veronique AU - Gigo V AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Marechal, Xavier AU - Marechal X AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Boet, Emeline AU - Boet E AD - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, Inserm, CNRS, 31100 Toulouse, France. AD - LabEx Toucan, 31100 Toulouse, France. AD - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, 31100 Toulouse, France. FAU - Sahal, Ambrine AU - Sahal A AUID- ORCID: 0000-0003-4755-2884 AD - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, Inserm, CNRS, 31100 Toulouse, France. AD - LabEx Toucan, 31100 Toulouse, France. AD - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, 31100 Toulouse, France. FAU - Alet, Nathalie AU - Alet N AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Abramovich, Ifat AU - Abramovich I AD - Technion-Israel Institute of Technology, Haifa 32000, Israel. FAU - Gottlieb, Eyal AU - Gottlieb E AD - Technion-Israel Institute of Technology, Haifa 32000, Israel. FAU - Visentin, Virgile AU - Visentin V AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Paillasse, Michael R AU - Paillasse MR AD - EVOTEC, Campus Curie, 31100 Toulouse, France. FAU - Sarry, Jean-Emmanuel AU - Sarry JE AUID- ORCID: 0000-0002-6704-2032 AD - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, Inserm, CNRS, 31100 Toulouse, France. AD - LabEx Toucan, 31100 Toulouse, France. AD - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, 31100 Toulouse, France. LA - eng PT - Journal Article DEP - 20210713 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC8306173 OTO - NOTNLM OT - AML OT - Immune checkpoints OT - OxPHOS COIS- R.L.-Y., J.M., V.G., N.A., V.V. and M.R.P. are full time employees of Evotec SE. The other authors declare no conflicting interests. EDAT- 2021/07/25 06:00 MHDA- 2021/07/25 06:01 PMCR- 2021/07/13 CRDT- 2021/07/24 01:01 PHST- 2021/06/07 00:00 [received] PHST- 2021/07/07 00:00 [revised] PHST- 2021/07/08 00:00 [accepted] PHST- 2021/07/24 01:01 [entrez] PHST- 2021/07/25 06:00 [pubmed] PHST- 2021/07/25 06:01 [medline] PHST- 2021/07/13 00:00 [pmc-release] AID - cancers13143499 [pii] AID - cancers-13-03499 [pii] AID - 10.3390/cancers13143499 [doi] PST - epublish SO - Cancers (Basel). 2021 Jul 13;13(14):3499. doi: 10.3390/cancers13143499.