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.
Keywords: Immunotherapy; Metabolic Networks and Pathways; Receptors, Chimeric Antigen; T-Lymphocytes.
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.