The metabolism of cells regulates their sensitivity to NK cells depending on p53 status
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 Natu...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-02-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-07281-6 |
| _version_ | 1818984973061849088 |
|---|---|
| author | Sana Belkahla Joaquin Marco Brualla Alexis Fayd’herbe de Maudave Paolo Falvo Nerea Allende-Vega Michael Constantinides Abrar Ul Haq Khan Lois Coenon Catherine Alexia Giulia Mitola Paul Massa Stefania Orecchioni Francesco Bertolini Wissem Mnif Javier Hernandez Alberto Anel Martin Villalba |
| author_facet | Sana Belkahla Joaquin Marco Brualla Alexis Fayd’herbe de Maudave Paolo Falvo Nerea Allende-Vega Michael Constantinides Abrar Ul Haq Khan Lois Coenon Catherine Alexia Giulia Mitola Paul Massa Stefania Orecchioni Francesco Bertolini Wissem Mnif Javier Hernandez Alberto Anel Martin Villalba |
| author_sort | Sana Belkahla |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T18:27:30Z |
| format | Article |
| id | doaj.art-0a6c7e5f1a1d4f84b4d02628999b7b05 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T18:27:30Z |
| publishDate | 2022-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0a6c7e5f1a1d4f84b4d02628999b7b052022-12-21T19:30:07ZengNature PortfolioScientific Reports2045-23222022-02-0112111310.1038/s41598-022-07281-6The metabolism of cells regulates their sensitivity to NK cells depending on p53 statusSana Belkahla0Joaquin Marco Brualla1Alexis Fayd’herbe de Maudave2Paolo Falvo3Nerea Allende-Vega4Michael Constantinides5Abrar Ul Haq Khan6Lois Coenon7Catherine Alexia8Giulia Mitola9Paul Massa10Stefania Orecchioni11Francesco Bertolini12Wissem Mnif13Javier Hernandez14Alberto Anel15Martin Villalba16PYD, King Faisal UniversityApoptosis, Immunity & Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón)IRMB, Univ Montpellier, INSERMLaboratory of Hematology-Oncology, IRCCS European Institute of OncologyIRMB, Univ Montpellier, INSERMIRMB, Univ Montpellier, INSERMIRMB, Univ Montpellier, INSERMIRMB, Univ Montpellier, INSERMIRMB, Univ Montpellier, INSERMLaboratory of Hematology-Oncology, IRCCS European Institute of OncologyLaboratory of Hematology-Oncology, IRCCS European Institute of OncologyLaboratory of Hematology-Oncology, IRCCS European Institute of OncologyLaboratory of Hematology-Oncology, IRCCS European Institute of OncologyDepartment of Chemistry, Faculty of Sciences and Arts in Balgarn, University of BishaIRMB, Univ Montpellier, INSERMApoptosis, Immunity & Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón)PYD, King Faisal UniversityAbstract 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.https://doi.org/10.1038/s41598-022-07281-6 |
| spellingShingle | Sana Belkahla Joaquin Marco Brualla Alexis Fayd’herbe de Maudave Paolo Falvo Nerea Allende-Vega Michael Constantinides Abrar Ul Haq Khan Lois Coenon Catherine Alexia Giulia Mitola Paul Massa Stefania Orecchioni Francesco Bertolini Wissem Mnif Javier Hernandez Alberto Anel Martin Villalba The metabolism of cells regulates their sensitivity to NK cells depending on p53 status Scientific Reports |
| title | The metabolism of cells regulates their sensitivity to NK cells depending on p53 status |
| title_full | The metabolism of cells regulates their sensitivity to NK cells depending on p53 status |
| title_fullStr | The metabolism of cells regulates their sensitivity to NK cells depending on p53 status |
| title_full_unstemmed | The metabolism of cells regulates their sensitivity to NK cells depending on p53 status |
| title_short | The metabolism of cells regulates their sensitivity to NK cells depending on p53 status |
| title_sort | metabolism of cells regulates their sensitivity to nk cells depending on p53 status |
| url | https://doi.org/10.1038/s41598-022-07281-6 |
| work_keys_str_mv | AT sanabelkahla themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT joaquinmarcobrualla themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT alexisfaydherbedemaudave themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT paolofalvo themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT nereaallendevega themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT michaelconstantinides themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT abrarulhaqkhan themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT loiscoenon themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT catherinealexia themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT giuliamitola themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT paulmassa themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT stefaniaorecchioni themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT francescobertolini themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT wissemmnif themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT javierhernandez themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT albertoanel themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT martinvillalba themetabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT sanabelkahla metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT joaquinmarcobrualla metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT alexisfaydherbedemaudave metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT paolofalvo metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT nereaallendevega metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT michaelconstantinides metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT abrarulhaqkhan metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT loiscoenon metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT catherinealexia metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT giuliamitola metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT paulmassa metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT stefaniaorecchioni metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT francescobertolini metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT wissemmnif metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT javierhernandez metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT albertoanel metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status AT martinvillalba metabolismofcellsregulatestheirsensitivitytonkcellsdependingonp53status |