1. GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.
- Author
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Sun RX, Liu YF, Sun YS, Zhou M, Wang Y, Shi BZ, Jiang H, and Li ZH
- Subjects
- Animals, Humans, Mice, Immunotherapy, Adoptive methods, Cell Line, Tumor, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Tumor Microenvironment, Apoptosis, Carcinoma, Hepatocellular therapy, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular metabolism, Liver Neoplasms immunology, Liver Neoplasms therapy, Liver Neoplasms pathology, Glucose Transporter Type 1 metabolism, Glypicans metabolism, Glypicans immunology
- Abstract
Chimeric antigen receptor-expressing T (CAR-T) cells induce robust antitumor responses in patients with hematologic malignancies. However, CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma (HCC), partially due to their limited expansion and persistence. CD8
+ T cells, as key components of the adaptive immune response, play a central role in antitumor immunity. Aerobic glycolysis is the main metabolic feature of activated CD8+ T cells. In the tumor microenvironment, however, the uptake of large amounts of glucose by tumor cells and other immunosuppressive cells can impair the activation of T cells. Only when tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment have a glycolytic advantage might the effector function of T cells be activated. Glucose transporter type 1 (GLUT1) and acylglycerol kinase (AGK) can boost glycolytic metabolism and activate the effector function of CD8+ T cells, respectively. In this study, we generated GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK for the treatment of HCC. GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK specifically and effectively lysed GPC3-positive tumor cells in vitro in an antigen-dependent manner. Furthermore, GLUT1 or AGK overexpression protected CAR-T cells from apoptosis during repeated exposures to tumor cells. Compared with second-generation CAR-T cells, GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK exhibited greater CD8+ T-cell persistence in vivo and better antitumor effects in HCC allograft mouse models. Finally, we revealed that GLUT1 or AGK maintained anti-apoptosis ability in CD8+ T cells via activation of the PI3K/Akt pathway. This finding might identify a therapeutic strategy for advanced HCC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)- Published
- 2024
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