Degradation of IKAROS prevents epigenetic progression of T cell exhaustion in a novel 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 that are phenotypically and transcriptionally similar to those found in human tumors. We performed a screen of human epigenetic regulators, identifying and validating IKAROS as a driver of T cell exhaustion. We found that the IKAROS degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving binding of AP-1, NF-κB, and NFAT. Thus, our study uncovered a role for IKAROS as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the potential use of iberdomide in solid tumors to prevent T cell exhaustion. Highlights ### Competing Interest Statement J.D.B. holds patents related to ATAC-seq and is an SAB member of Camp4 and seqWell. G.B., E.J. A.G., I.K.R., A.D., L.P., J.K., M.G.O., S.F., S.C. and D.A.M. are current or former employees of AstraZeneca. V.B.W. is an employee of Revvity. S.L.T. was formerly an employee of Revvity.