journal contribution
posted on 2023-04-04, 01:07 authored by Junmei Wang, Farah Hasan, Amanda C. Frey, Haiyan S. Li, Jungsun Park, Ke Pan, Cara Haymaker, Chantale Bernatchez, Dean A. Lee, Stephanie S. Watowich, Cassian Yee Supplementary Figures and Legends
Funding
Parker Institute for Cancer Immunotherapy
Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team Translational Cancer Research
Entertainment Industry Foundation
American Association for Cancer Research
NIAID
NCI
History
ARTICLE ABSTRACT
Clinical response rates after adoptive cell therapy (ACT) are highly correlated with in vivo 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 CD28 promoter region. This led to IL21-mediated pSTAT3 binding to the CD28 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 Lef1 and Tcf7). Our findings support the application of IL21 and HDACi for the in vitro generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.
