ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes

Cell Metab. 2022 Sep 6;34(9):1342-1358.e7. doi: 10.1016/j.cmet.2022.08.007.


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.

Keywords: ATF3; CD8(+) T lymphocytes; CH25H; cancer immunotherapy; chimeric antigen receptor; cytotoxic T lymphocytes; hydroxycholesterol; sumoylation inhibitor; trogocytosis; tumor-derived factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Immunotherapy
  • Steroid Hydroxylases
  • T-Lymphocytes, Cytotoxic*
  • Trogocytosis*
  • Virus Replication / genetics


  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase