Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell-Intrinsic Dysfunction

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hema-tologic cancers, but resistance is common and effi cacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knock-out not only blocks this type I interferon-mediated inhibitory program but also independently expands early memory CAR T cells with improved effi cacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-& beta; exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I inter-feron signaling. Finally, a refi ned EGR2 gene signature is a biomarker for type I interferon-associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinfl ammatory signaling and point to an EGR2-type I interferon axis as a thera-peutically amenable biological system.SIGNIFICANCE: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell-intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway-induced dysfunction and improves memory differen-tiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies.

Automated summary

CAR T cell therapy has shown potential in treating hematologic cancers but is limited in solid tumors. Chronic stimulation of CAR T cells propagates inhibitory type I interferon signaling, hindering antitumor function. Knocking out the EGR2 transcriptional regulator improves CAR T cell efficacy and blocks interferon-induced dysfunction. The gene signature of EGR2 is a biomarker for CAR T cell failure and patient survival. Modulating CAR T cell-intrinsic resistance is crucial for improving therapy outcomes.