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

Effector trogocytosis between malignant cells and tumor-specific cytotoxic T lymphocytes (CTLs) contrib-utes 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 demon-strate that tumor-derived factors (TDFs) stimulated effector trogocytosis and restricted CTLs' tumoricidal ac-tivity 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 immuno-therapies.

Automated summary

The factors derived from tumors affect the activity and viability of tumor-specific cytotoxic T lymphocytes (CTLs), but the underlying mechanism is not well understood. These tumor-derived factors alter the lipid composition of cells and regulate the effector trogocytosis between cells. This process is controlled by the ATF3-CH25H axis, which affects tumor immunity, tumor growth, and the efficacy of CAR cell therapy.