التفاصيل البيبلوغرافية
| العنوان: |
Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism. |
| المؤلفون: |
Quanjun Yang, Juan Hao, Mengyi Chi, Yaxian Wang, Bo Xin, Jinglu Huang, Jin Lu, Jie Li, Xipeng Sun, Chunyan Li, Yan Huo, Jianping Zhang, Yonglong Han, Cheng Guo |
| المصدر: |
OncoImmunology; 2022, Vol. 11 Issue 1, p1-14, 14p |
| مصطلحات موضوعية: |
KYNURENINE, T cells, CHIMERIC antigen receptors, METABOLISM, CANCER cells, GRANZYMES |
| مستخلص: |
Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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