Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.

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Publication Details

Journal
Cell Reports Medicine
Published
2024-10-31
DOI
https://doi.org/10.1016/j.xcrm.2024.101804
Citations
9
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
2.16

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article

Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay

Deanna A. Mele, Sin Lih Tan, Steven W. Criscione, Laura B. Prickett et al.
9 citations
Cell Reports Medicine
Immune Cell Function and Interaction
2.16
article

Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay

Deanna A. Mele, Sin Lih Tan, Steven W. Criscione, Laura B. Prickett, Michael G. Overstreet, James Kurasawa, Tristan Tay, Yan Hu, Gayathri Bommakanti, Verena Brucklacher-Waldert, Aparna Gorthi, Jason D. Buenrostro, Elizabeth Jaensch, Aatman S. Doshi, Iswarya Karapa Reddy, Ruochi Zhang
article en
9 citations

Abstract

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.

Cell Reports MedicineVol. 5(11)
AstraZeneca (South Korea) (KR), AstraZeneca (Brazil) (BR), AstraZeneca (United States) (US), Harvard Stem Cell Institute (US)
National Science Foundation, AstraZeneca, National Institutes of Health
Zero hunger
Openalex Percentile: Top 12%
Immune Cell Function and Interaction
2.16
DOIOpen Access PDFOpenAlex
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