Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Nerea Allende-Vega (1) , Joaquin Marco Brualla (2) , Paolo Falvo (3) , Catherine Alexia (1) , Michael Constantinides (1) , Alexis Fayd’herbe de Maudave (1) , Lois Coenon (1) , Delphine Gitenay (1) , Giulia Mitola (3) , Paul Massa (3) , Stefania Orecchioni (3) , Francesco Bertolini (3) , Isabel Marzo (2) , Alberto Anel (2) , Martin Villalba (1, 4, 5)

1 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
2 University of Zaragoza - Universidad de Zaragoza [Zaragoza]
3 ESMO - European Institute of Oncology [Milan]
4 Institut Sainte Catherine [Avignon]
5 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]

Abstract Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic 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 anti-apoptotic 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.

Mots clés: Cancer; Immunology

Domaines: Sciences du Vivant [q-bio]

Nerea Allende-Vega, Joaquin Marco Brualla, Paolo Falvo, Catherine Alexia, Michael Constantinides, et al.. Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1). Scientific Reports, 2022, 12 (1), pp.1341. ⟨10.1038/s41598-022-05470-x⟩. ⟨hal-03564112⟩