BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models
Yuki Kagoya, … , Cheryl H. Arrowsmith, Naoto Hirano
Yuki Kagoya, … , Cheryl H. Arrowsmith, Naoto Hirano
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3479-3494. https://doi.org/10.1172/JCI86437.
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BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models

Abstract

Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell–like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8+ T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy.

Authors

Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, Cheryl H. Arrowsmith, Naoto Hirano

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Figure 2

JQI, a BET bromodomain inhibitor, maintains CD8+ T cells with features of stem cell–like and central memory T cells.

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JQI, a BET bromodomain inhibitor, maintains CD8+ T cells with features o...
(A) Frequency of CD45RA+/–CD62L+CCR7+ cells within the CD8+ T cell population cultured for 14 days in the presence of JQ1 or (–)-JQ1 (n = 7, paired t test). (B) Expression of CD27, CD28, CD127, and CD95 in the CD8+ T cells cultured in the presence of JQ1 or (–)-JQ1. Representative FACS plots of the samples shown in A. (C and D) CD45RA+CD62L+CCR7+ T cells were stimulated weekly with aAPC/mOKT3 and cultured with or without JQ1. Representative FACS plots of CD45RA, CD62L, and CCR7 expression at the indicated time points (C) as well as the frequency of CD45RA+/–CD62L+CCR7+ cells within the CD8+ T cell population 21 days following initial stimulation (D) are shown (n = 5, paired t test). (E and F) The secretion of IL-2, IFN-γ, and TNF-α was evaluated by intracellular flow cytometry in CD8+CD45RA+CD62L+CCR7+ T cells cultured for 14 days with or without JQ1. The frequency of each cytokine-producing cell type (E) and those secreting all 3 cytokines (F) are shown (n = 5, paired t test). (G) Expression profiles of representative genes with differential expression between the TSCM/TCM and TEM phenotypes. Fold expression levels in JQ1-treated CD8+ T cells relative to those in the control T cells are shown (n = 4). Error bars indicate the SD. (H) CD3+ T cells isolated from HLA-A2+ donors were stimulated by artificial antigen-presenting cells that express HLA-A*02:01, CD80, and CD83 (aAPC/A2) and were pulsed with the MART127–35 peptide once per week. The frequency of CD45RA+/–CD62L+CCR7+ cells within the A2/MART1 multimer+ CD8+ T cell population 21 days after initial stimulation is shown (n = 4, paired t test). NS, not significant.