Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies
Background Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facil...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/6/e006287.full |
| _version_ | 1827207694516224000 |
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| author | Sergio Quezada Ernesto Lopez Rajesh Karattil Francesco Nannini Gordon Weng-Kit Cheung Lilian Denzler Felipe Galvez-Cancino Martin A Pule |
| author_facet | Sergio Quezada Ernesto Lopez Rajesh Karattil Francesco Nannini Gordon Weng-Kit Cheung Lilian Denzler Felipe Galvez-Cancino Martin A Pule |
| author_sort | Sergio Quezada |
| collection | DOAJ |
| description | Background Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facilitated by expression of monocarboxylate transporter (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 on activation, while certain tumors predominantly express MCT-1.Methods Here, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma.Results MCT-1 inhibition with small molecules AZD3965 or AR-C155858 induced CAR T-cell metabolic rewiring but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade.Conclusion This work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies. |
| first_indexed | 2024-03-12T21:53:47Z |
| format | Article |
| id | doaj.art-10429564487849308965fd1a353ff5d2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2025-03-21T12:44:08Z |
| publishDate | 2023-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-10429564487849308965fd1a353ff5d22024-06-27T07:15:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-06-0111610.1136/jitc-2022-006287Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignanciesSergio Quezada0Ernesto Lopez1Rajesh Karattil2Francesco Nannini3Gordon Weng-Kit Cheung4Lilian Denzler5Felipe Galvez-Cancino6Martin A Pule7Cancer Immunology Unit, Cancer Institute, University College London, London, UKHaematology Department, Cancer Institute, University College London, London, UKHaematology Department, Cancer Institute, University College London, London, UKCancer Immunology Unit, Cancer Institute, University College London, London, UKHaematology Department, Cancer Institute, University College London, London, UKDivision of Biosciences, Institute of Structural and Molecular Biology, University College London, London, UKCancer Immunology Unit, Cancer Institute, University College London, London, UKResearch Department of Haematology, University College London, London, UKBackground Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facilitated by expression of monocarboxylate transporter (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 on activation, while certain tumors predominantly express MCT-1.Methods Here, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma.Results MCT-1 inhibition with small molecules AZD3965 or AR-C155858 induced CAR T-cell metabolic rewiring but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade.Conclusion This work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies.https://jitc.bmj.com/content/11/6/e006287.full |
| spellingShingle | Sergio Quezada Ernesto Lopez Rajesh Karattil Francesco Nannini Gordon Weng-Kit Cheung Lilian Denzler Felipe Galvez-Cancino Martin A Pule Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies Journal for ImmunoTherapy of Cancer |
| title | Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies |
| title_full | Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies |
| title_fullStr | Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies |
| title_full_unstemmed | Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies |
| title_short | Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies |
| title_sort | inhibition of lactate transport by mct 1 blockade improves chimeric antigen receptor t cell therapy against b cell malignancies |
| url | https://jitc.bmj.com/content/11/6/e006287.full |
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