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Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T cell-intrinsic Dysfunction (RNA-Seq)

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in the treatment of hematopoietic cancers, but resistance is common, and efficacy is limited in solid tumors. We demonstrate that CAR T-cells autonomously propagate epigenetically-programmed type I interferon signaling through chronic stimulation or antigen-independent tonic activation, which progressively hampers antitumor effector function. EGR2 transcriptional regulator knockoutnot only blocks this type I interferon-mediated inhibitory program, but also independently expands early memory CAR T-cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T-cells against chronic antigen-induced dysfunction can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses CAR T-cell dysfunction through inhibition of type I interferon signaling. Finally, enrichment of an EGR2 gene signature is a clinical biomarker for type I interferon-associated CAR T-cell failure and shorter overall patient survival. These findings conceptually connect prolonged CAR T-cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biologic system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224193 | GEO | 2023/02/20

REPOSITORIES: GEO

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Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T cell-intrinsic Dysfunction (ATAC-Seq)

Project description:Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in the treatment of hematopoietic cancers, but resistance is common, and efficacy is limited in solid tumors. We demonstrate that CAR T-cells autonomously propagate epigenetically-programmed type I interferon signaling through chronic stimulation or antigen-independent tonic activation, which progressively hampers antitumor effector function. EGR2 transcriptional regulator knockoutnot only blocks this type I interferon-mediated inhibitory program, but also independently expands early memory CAR T-cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T-cells against chronic antigen-induced dysfunction can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses CAR T-cell dysfunction through inhibition of type I interferon signaling. Finally, enrichment of an EGR2 gene signature is a clinical biomarker for type I interferon-associated CAR T-cell failure and shorter overall patient survival. These findings conceptually connect prolonged CAR T-cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biologic system.

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