Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Version 1 : Received: 19 July 2021 / Approved: 21 July 2021 / Online: 21 July 2021 (10:54:14 CEST)

How to cite: Allende-Vega, N.; Marco Brualla, J.; Falvo, P.; Alexia, C.; Constantinides, M.; Fayd-Herbe-de-Maudave, A.; coenon, L.; gitenay, D.; Mitola, G.; massa, P.; orecchioni, S.; Bertolini, F.; Marzo, I.; Anel, A.; Villalba, M. Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1). Preprints 2021, 2021070484 (doi: 10.20944/preprints202107.0484.v1). Allende-Vega, N.; Marco Brualla, J.; Falvo, P.; Alexia, C.; Constantinides, M.; Fayd-Herbe-de-Maudave, A.; coenon, L.; gitenay, D.; Mitola, G.; massa, P.; orecchioni, S.; Bertolini, F.; Marzo, I.; Anel, A.; Villalba, M. Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1). Preprints 2021, 2021070484 (doi: 10.20944/preprints202107.0484.v1).

Abstract

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

Keywords

metformin; Natural Killer cells; Cytotoxic T lymphocytes; intercellular adhesion molecule-1 (ICAM-1); Natural Killer G2-D (NKG2D) ligands (NKG2DL); lymphocyte function-associated antigen 1 (LFA-1)

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