Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay
Tristan Tay, Gayathri Bommakanti, Elizabeth Jaensch, Aparna Gorthi, Iswarya Karapa Reddy, Yan Hu, Ruochi Zhang, Aatman S. Doshi, Sin Lih Tan, Verena Brucklacher-Waldert, Laura B. Prickett, James Kurasawa, Michael G. Overstreet, Steven W. Criscione, Jason D. Buenrostro, Deanna A. Mele
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. • In vitro assay generates antigen-specific exhausted T cells from human T cells • IKZF1 (IKAROS) is a key driver of T cell exhaustion • Iberdomide (IKZF1/3 degrader) prevents the progression of exhaustion • IKZF1 silences effector genes by inhibiting AP-1, NF-κB, and NFAT binding Tay et al. demonstrate an antigen-specific assay producing exhausted T cells that reflect those found in human tumors. They identify IKZF1 (IKAROS) as a driver of exhaustion progression and validate that the IKZF1 degrader iberdomide is sufficient to preserve effector function by preventing IKZF1-induced silencing of effector gene enhancers.