Journal article
ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes
Cell metabolism, v 34(9), pp 1342-1358.e7
06 Sep 2022
PMID: 36070682
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes
- Creators
- Zhen Lu - University of PennsylvaniaNoreen McBrearty - University of PennsylvaniaJinyun Chen - University of PennsylvaniaVivek S Tomar - University of PennsylvaniaHongru Zhang - University of PennsylvaniaGianluca De Rosa - University of PennsylvaniaAiwen Tan - University of PennsylvaniaAalim M Weljie - University of PennsylvaniaDaniel P Beiting - University of PennsylvaniaZhen Miao - University of PennsylvaniaSubin S George - University of PennsylvaniaAllison Berger - Takeda (United States)Gurpanna Saggu - Takeda (United States)J Alan Diehl - Case Western Reserve UniversityConstantinos Koumenis - University of PennsylvaniaSerge Y Fuchs - University of Pennsylvania
- Publication Details
- Cell metabolism, v 34(9), pp 1342-1358.e7
- Publisher
- Elsevier
- Grant note
- R01 CA247803 / NCI NIH HHS T32 CA115299 / NCI NIH HHS P01 CA165997 / NCI NIH HHS R01 CA240814 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000862266800002
- Scopus ID
- 2-s2.0-85137456072
- Other Identifier
- 991022004877004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Cell Biology
- Endocrinology & Metabolism