ATF3 and CH25H Regulate Effector Trogocytosis and Anti-tumor Activities of Endogenous and Immunotherapeutic Cytotoxic T Lymphocytes

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2022 Sep 7

PMID 36070682

Authors

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

Affiliations

Soon will be listed here.

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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