The metabolism of cells regulates their sensitivity to NK cells depending on p53 status

Sana Belkahla (1, 2) , Joaquin Marco Brualla (3, 4) , Alexis Fayd’herbe de Maudave (2) , Paolo Falvo (5) , Nerea Allende-Vega (2) , Michael Constantinides (2) , Abrar Ul Haq Khan (2) , Lois Coenon (2) , Catherine Alexia (2) , Giulia Mitola (5) , Paul Massa (5) , Stefania Orecchioni (5) , Francesco Bertolini (5) , Wissem Mnif (6, 7) , Javier Hernandez (2) , Alberto Anel (3) , Martin Villalba (2, 1, 8)

1 KFU - King Faisal University
2 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
3 University of Zaragoza - Universidad de Zaragoza [Zaragoza]
4 Aragón Health Research Institute [Zaragoza, Spain]
5 Medical Oncology Unit, Dept of Medical Oncology and Hematology [Fondazione IRCCS Istituto Nazionale Tumori, Milan]
6 University of Bisha [Balgarn]
7 UMA - Université de la Manouba [Tunisie]
8 Institut Sainte Catherine [Avignon]

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.

Mots clés: Biotechnology; Cancer; Immunology

Domaines: Cancer

Sana Belkahla, Joaquin Marco Brualla, Alexis Fayd’herbe de Maudave, Paolo Falvo, Nerea Allende-Vega, et al.. The metabolism of cells regulates their sensitivity to NK cells depending on p53 status. Scientific Reports, 2022, 12 (1), pp.3234. ⟨10.1038/s41598-022-07281-6⟩. ⟨hal-03595038⟩