Bibliographic Details
| Title: |
Impaired T cell proliferation by ex vivoBET-inhibition impedes adoptive immunotherapy in a murine melanoma model |
| Authors: |
Chee, Jonathan, Wilson, Chelsea, Buzzai, Anthony, Wylie, Ben, Forbes, Catherine A, Booth, Mitchell, Principe, Nicola, Foley, Bree, Cruickshank, Mark N, Waithman, Jason |
| Source: |
Epigenetics; February 2020, Vol. 15 Issue: 1-2 p134-144, 11p |
| Abstract: |
ABSTRACTActivation of naïve CD8+T cells stimulates proliferation and differentiation into cytotoxic T-lymphocytes (CTLs). Adoptive T Cell Therapy (ACT) involves multiple rounds of ex vivoactivation to generate enough CTLs for reinfusion into patients, but this drives differentiation into terminal effector T cells. Less differentiated CTL populations, such as stem cell memory T cells, are more ideal candidates for ACT because of increased self-renewal and persistent properties. Ex vivotargeting of T cell differentiation with epigenetic modifiers is a potential strategy to improve cytotoxic T-lymphocyte (CTL) generation for ACT. We established a pipeline to assess the effects of epigenetic modifiers on CD8+T cell proliferation, differentiation, and efficacy in a preclinical melanoma model. Single treatment with epigenetic modifiers inhibited T cell proliferation in vitro, producing CD44hiCD62Lhieffector-like T cells rather than a stem cell memory T cell phenotype. Most epigenetic modifying agents had no significant effect on ACT efficacy with the notable exception of the bromodomain and extraterminal (BET)-inhibitor JQ1 which was associated with a decrease in efficacy compared to unmodified T cells. These findings reveal the complexity of epigenetic targeting of T cell differentiation, highlighting the need to precisely define the epigenetic targeting strategies to improve CTL generation for ACT. |
| Database: |
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