期刊
CANCER IMMUNOLOGY RESEARCH
卷 8, 期 6, 页码 794-805出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-19-0619
关键词
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资金
- Parker Institute for Cancer Immunotherapy
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team Translational Cancer Research grant [SU2C-AACR-DT1012]
- NIH National Institute of Allergy and Infectious Diseases (NIAID) [RO1AI109294]
- NCI [P30CA016672]
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.
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