1. The metabolism of cells regulates their sensitivity to NK cells depending on p53 status.
- Author
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Belkahla, Sana, Brualla, Joaquin Marco, Fayd'herbe de Maudave, Alexis, Falvo, Paolo, Allende-Vega, Nerea, Constantinides, Michael, Khan, Abrar Ul Haq, Coenon, Lois, Alexia, Catherine, Mitola, Giulia, Massa, Paul, Orecchioni, Stefania, Bertolini, Francesco, Mnif, Wissem, Hernandez, Javier, Anel, Alberto, and Villalba, Martin
- Subjects
KILLER cells ,CYTOTOXIC T cells ,CELL metabolism ,P53 antioncogene ,CELLULAR recognition ,IMMUNE recognition - Abstract
Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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