Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8 T Cells to Memory T Cells.

Clinical response rates after adoptive cell therapy (ACT) are highly correlated with persistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8 T cells, capable of self-renewal, represent desirable ACT products. We report here that exposure to a histone deacetylase inhibitor (HDACi) and IL21 could reprogram differentiated human CD8 T cells into central memory-like T cells. Dedifferentiation of CD8 T cells was initiated by increased H3 acetylation and chromatin accessibility at the promoter region. This led to IL21-mediated pSTAT3 binding to the region, and subsequent upregulation of surface CD28 and CD62L (markers of central memory T cells). The reprogrammed cells exhibited enhanced proliferation in response to both IL2 and IL15, and a stable memory-associated transcriptional signature (increased and ). Our findings support the application of IL21 and HDACi for the generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.