Impaired T cell proliferation by ex vivo BET-inhibition impedes adoptive immunotherapy in a murine melanoma model

Jonathan Chee, Chelsea Wilson, Anthony Buzzai, Ben Wylie, Catherine A Forbes, Mitchell Booth, Nicola Principe, Bree Foley, Mark N Cruickshank, Jason Waithman

Research output: Contribution to journalArticle

Abstract

Activation of naïve CD8+ T cells stimulates proliferation and differentiation into cytotoxic T-lymphocytes (CTLs). Adoptive T Cell Therapy (ACT) involves multiple rounds of ex vivo activation 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 vivo targeting 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 CD44hiCD62Lhi effector-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.
Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalEpigenetics
DOIs
Publication statusE-pub ahead of print - 26 Aug 2019

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Adoptive Immunotherapy
Melanoma
Cell Proliferation
T-Lymphocytes
Epigenomics
Cytotoxic T-Lymphocytes
Cell- and Tissue-Based Therapy
Cell Differentiation
Stem Cells

Cite this

Chee, Jonathan ; Wilson, Chelsea ; Buzzai, Anthony ; Wylie, Ben ; Forbes, Catherine A ; Booth, Mitchell ; Principe, Nicola ; Foley, Bree ; Cruickshank, Mark N ; Waithman, Jason. / Impaired T cell proliferation by ex vivo BET-inhibition impedes adoptive immunotherapy in a murine melanoma model. In: Epigenetics. 2019 ; pp. 1-11.
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Impaired T cell proliferation by ex vivo BET-inhibition impedes adoptive immunotherapy in a murine melanoma model. / Chee, Jonathan; Wilson, Chelsea; Buzzai, Anthony; Wylie, Ben; Forbes, Catherine A; Booth, Mitchell; Principe, Nicola; Foley, Bree; Cruickshank, Mark N; Waithman, Jason.

In: Epigenetics, 26.08.2019, p. 1-11.

Research output: Contribution to journalArticle

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AU - Booth, Mitchell

AU - Principe, Nicola

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AU - Cruickshank, Mark N

AU - Waithman, Jason

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