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Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies

Lopez, Ernesto; Karattil, Rajesh; Nannini, Francesco; Weng-Kit Cheung, Gordon; Denzler, Lilian; Galvez-Cancino, Felipe; Quezada, Sergio; (2023) Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies. Journal for ImmunoTherapy of Cancer , 11 (6) , Article e006287. 10.1136/jitc-2022-006287. Green open access

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Abstract

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.

Type: Article
Title: Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/jitc-2022-006287
Publisher version: http://dx.doi.org/10.1136/jitc-2022-006287
Language: English
Additional information: This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
Keywords: Immunotherapy, Metabolic Networks and Pathways, Receptors, Chimeric Antigen, T-Lymphocytes, Animals, Mice, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Lymphoma, B-Cell, Lactates, Cell- and Tissue-Based Therapy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10172959
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