Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

Version 1 : Received: 7 June 2021 / Approved: 9 June 2021 / Online: 9 June 2021 (10:58:20 CEST)

How to cite: Luna-Yolba, R.; Marmoiton, J.; Gigo, V.; Marechal, X.; Boet, E.; Sahal, A.; Alet, N.; Abramovich, I.; Gottlieb, E.; Visentin, V.; Paillasse, M.R.; Sarry, J. Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells. Preprints 2021, 2021060256 (doi: 10.20944/preprints202106.0256.v1). Luna-Yolba, R.; Marmoiton, J.; Gigo, V.; Marechal, X.; Boet, E.; Sahal, A.; Alet, N.; Abramovich, I.; Gottlieb, E.; Visentin, V.; Paillasse, M.R.; Sarry, J. Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells. Preprints 2021, 2021060256 (doi: 10.20944/preprints202106.0256.v1).

Abstract

Abstract: 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 antitumor response. Modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve 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 the ecto-nucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemoresistance and poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that, while AraC induced immune response regulation by increasing CD39 expression and by reinforcing interferon-γ/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.

Subject Areas

OxPHOS 1; Immune-checkpoints 2; AML 3.

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