期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 11, 期 6, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-006287
关键词
Immunotherapy; Metabolic Networks and Pathways; Receptors; Chimeric Antigen; T-Lymphocytes
The combination of CAR T-cell therapy and MCT-1 blockade demonstrates improved cytotoxicity and antitumoral control in B-cell lymphoma, indicating the potential of targeting lactate metabolism in CAR T-cell therapies.
BackgroundChimeric 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. MethodsHere, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma. ResultsMCT-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. ConclusionThis work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies.
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