Figure S7 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T cell-intrinsic Dysfunction

Jung, In-Young; Bartoszek, Robert L.; Rech, Andrew J.; Collins, Sierra M.; Ooi, Soon-Keat; Williams, Erik F.; Hopkins, Caitlin R.; Narayan, Vivek; Haas, Naomi B.; Frey, Noelle V.; Hexner, Elizabeth O.; Siegel, Donald L.; Plesa, Gabriela; Porter, David L.; Cantu, Adrian; Everett, John K.; Guedan, Sonia; Berger, Shelley L.; Bushman, Frederic D.; Herbst, Friederike; Fraietta, Joseph A.

doi:10.1158/2159-8290.27025277.v1

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Figure S7 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T cell-intrinsic Dysfunction

journal contribution

posted on 2024-09-16, 09:31 authored by In-Young Jung, Robert L. Bartoszek, Andrew J. Rech, Sierra M. Collins, Soon-Keat Ooi, Erik F. Williams, Caitlin R. Hopkins, Vivek Narayan, Naomi B. Haas, Noelle V. Frey, Elizabeth O. Hexner, Donald L. Siegel, Gabriela Plesa, David L. Porter, Adrian Cantu, John K. Everett, Sonia Guedan, Shelley L. Berger, Frederic D. Bushman, Friederike Herbst, Joseph A. Fraietta

Gene expression and pathway enrichment analysis of CD4+ T cell clusters. (A) Heatmap showing differentially expressed genes between AAVS1 and EGR2 knockout (KO) CD4+ T-cells. (B-D) Top differentially regulated pathways in CD4+ EGR2 KO compared to AAVS1 KO CAR T-cells. Pathways were explored using: B, GO biological process. C, NCI-Nature Pathway Interaction Database 2015. D, ARCHS4 transcription factor (TF) co-expression.

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ARTICLE ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in treating hematological cancers, but resistance is common, and efficacy 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 knockout not 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 exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined 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 immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biologic system.