| Autor: |
Zhen Lu, Noreen McBrearty, Jinyun Chen, Vivek S. Tomar, Hongru Zhang, Gianluca De Rosa, Aiwen Tan, Aalim M. Weljie, Daniel P. Beiting, Zhen Miao, Subin S. George, Allison Berger, Gurpanna Saggu, J. Alan Diehl, Constantinos Koumenis, Serge Y. Fuchs |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cell Metabolism. 34:1342-1358.e7 |
| ISSN: |
1550-4131 |
| Popis: |
Effector trogocytosis between malignant cells and tumor-specific cytotoxic T lymphocytes (CTLs) contributes to immune evasion through antigen loss on target cells and fratricide of antigen-experienced CTLs by other CTLs. The mechanisms regulating these events in tumors remain poorly understood. Here, we demonstrate that tumor-derived factors (TDFs) stimulated effector trogocytosis and restricted CTLs' tumoricidal activity and viability in vitro. TDFs robustly altered the CTL's lipid profile, including depletion of 25-hydroxycholesterol (25HC). 25HC inhibited trogocytosis and prevented CTL's inactivation and fratricide. Mechanistically, TDFs induced ATF3 transcription factor that suppressed the expression of 25HC-regulating gene-cholesterol 25-hydroxylase (CH25H). Stimulation of trogocytosis in the intratumoral CTL by the ATF3-CH25H axis attenuated anti-tumor immunity, stimulated tumor growth, and impeded the efficacy of chimeric antigen receptor (CAR) T cell adoptive therapy. Through use of armored CAR constructs or pharmacologic agents restoring CH25H expression, we reversed these phenotypes and increased the efficacy of immunotherapies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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