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ATM-AMPKα mediated LAG-3 expression suppresses T cell function in prostate cancer.
- Source :
-
Cellular Immunology . Nov2023, Vol. 393, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
-
Abstract
- • LAG3 upregulation inhibits effector function of CD4 T -cells from PCa. • Insufficiency expression of ATM upregulates LAG3 expression in PCa. • ATM dysfunction impairs AMPKα which enhances the binding of EGR2 and XBP1 to LAG3 promoters. • Blocking EGR2/XBP1 or restoring ATM-AMPKα aid in the cancer immunotherapy for PCa. Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4+ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4+ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4+ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00088749
- Volume :
- 393
- Database :
- Academic Search Index
- Journal :
- Cellular Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 173967443
- Full Text :
- https://doi.org/10.1016/j.cellimm.2023.104773