Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [bulk ATAC-seq]

Epigenetic regulation drives the differentiation of T cells into phenotypically stable subsets including a dysfunctional state termed exhaustion, the presence of these epigenetically distinct T cells in tumors make them non-responsive to checkpoint blockade. Cancer immunotherapies restoring T cell function have transformed cancer treatment by preventing immune evasion of tumor cells allowed by T cell exhaustion. However, some patients develop resistance to immunotherapy or do not respond. Recent literature has demonstrated that epigenetic regulation governs the transition from effector to exhausted T cells. Here, we describe a novel antigen-specific assay for T-cell exhaustion that produces T cells biologically and epigenetically similar to their in vivo exhausted counterpart. We perform a CRISPR KO screen for epigenetic regulators of the human genome and validate Ikaros as a driver of T-cell exhaustion. We determined that the Ikaros degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers by preserving activity of key transcription factors AP-1, NF-κB and NFAT using transcription factor footprinting analysis. Thus, our study uncovers a role for Ikaros, degraded by the drug iberdomide, as a driver of T-cell exhaustion.