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

Abstract

Clinical response rates after adoptive cell therapy (ACT) are highly correlated with <i>in vivo</i> 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 <i>CD28</i> promoter region. This led to IL21-mediated pSTAT3 binding to the <i>CD28</i> 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 <i>Lef1</i> and <i>Tcf7</i>). Our findings support the application of IL21 and HDACi for the <i>in vitro</i> generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.