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

In-Young Jung1,2,3,4, Robert L Bartoszek1,2,3,4, Andrew J Rech2,4,5,6

  • 1Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Cancer Discovery
|April 3, 2023
PubMed

Insights

Deleting the EGR2 gene in CAR T cells prevents dysfunction caused by interferon signaling, enhancing their effectiveness against both liquid and solid tumors. This discovery offers a new therapeutic target for improving CAR T cell cancer therapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Chimeric antigen receptor (CAR) T cell therapy shows promise for hematologic cancers but faces resistance and limited efficacy in solid tumors.
  • CAR T cells can develop dysfunction due to chronic stimulation, leading to epigenetic programming of type I interferon signaling.
  • Intrinsic resistance mechanisms in CAR T cells hinder therapeutic outcomes.

Purpose of the Study:

  • To investigate the role of the EGR2 transcriptional regulator in CAR T cell dysfunction.
  • To explore EGR2 as a target for enhancing CAR T cell efficacy in various cancer types.
  • To identify biomarkers for predicting CAR T cell therapy failure.

Main Methods:

  • Utilized gene editing techniques to knock out the EGR2 transcriptional regulator in CAR T cells.
  • Assessed the impact of EGR2 knockout on CAR T cell function, memory differentiation, and antitumor efficacy in preclinical models.
  • Analyzed the relationship between EGR2, type I interferon signaling, and patient survival.

Main Results:

  • EGR2 knockout blocked type I interferon-mediated inhibitory signaling in CAR T cells.
  • EGR2 deletion promoted the expansion of early memory CAR T cells, improving efficacy against liquid and solid tumors.
  • EGR2 ablation suppressed CAR T cell dysfunction, which could be overridden by interferon-β exposure.
  • A specific EGR2 gene signature was identified as a biomarker for type I interferon-associated CAR T cell failure and reduced patient survival.

Conclusions:

  • EGR2 acts as a key regulator of type I interferon-induced dysfunction in CAR T cells.
  • Targeting the EGR2-type I interferon axis presents a promising therapeutic strategy to overcome CAR T cell resistance.
  • EGR2 gene editing enhances CAR T cell memory differentiation and antitumor activity, offering potential improvements for cancer immunotherapy.

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