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.
Highlights
Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes
We investigated if p53 status can affect the effect of metformin on ligands that are recognized by cytotoxic lymphocytes
We treated with 2 mM metformin for 3 days 3 acute myeloid leukemia (AML) cell lines with different p53 status (OCI-AML3 cells express wt p53, HL60 are p53 null and NB4 express mutant p 5320,29) and analyzed MHC Class I Polypeptide-Related Sequence A (MICA)/B and ULBP1 expression on plasma membrane
Summary
Metformin regulates expression of stress ligands and ICAM‐1 in leukemic cells. We have previously shown in several studies that the presence of wtp[53] impacts the effect of several co-treatments involving the so-called metabolic drugs, e.g. metformin[20,27,28]. It did not increase expression of HLA, the B cell marker CD20 or the death receptors Fas, DR4 or DR5. We treated with metformin the primary cells from a B-cell lymphoma patient (BCL-P2) and observed that it significantly increased expression of ULBP1 and ICAM-1 and tended to increase MICA/B and CD20 expression (Fig. 5A and Supplemental Fig. 4). When we used a construct (D1D2) that binds to LFA-1 and blocks its binding to ICAM-124, we observed a significant reduction in cell killing in metformintreated cells in three leukemic cell types, including primary BCL-P2 cells (Fig. 6B) We used another set of antibodies to block the interaction of these receptors with their ligands (Fig. 6C). ***p < 0.001 Student’s t-test compared to cells not treated with metformin
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