BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models
Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, Cheryl H. Arrowsmith, Naoto Hirano
Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, Cheryl H. Arrowsmith, Naoto Hirano
View: Text | PDF
Research Article Immunology

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

×

Figure 5

JQ1 treatment improves the antitumor activity of T cell receptor–transduced T cells.

Options: View larger image (or click on image) Download as PowerPoint
JQ1 treatment improves the antitumor activity of T cell receptor–transdu...
(A) CD3+ T cells were retrovirally transduced with HLA-A2/MART127–35 TCR (clone DMF5) and cultured in the presence of JQ1 or (–)-JQ1. The drugs were removed on day 14, and the functional properties of the A2/MART1 T cells were analyzed. (B) DMF5-transduced T cells generated in the presence of JQ1 or (–)-JQ1 were serially stimulated with aAPC/A2 pulsed with MART127–35 peptide, and the fold expansion of the CD8+ A2/MART1 cells was calculated at the indicated time points (n = 4, paired t test). Error bars indicate the SD. (C and D) JQ1-DMF5 and (–)-JQ1-DMF5 T cells were labeled with CFSE and stimulated with aAPC/A2 pulsed with MART127–35 peptide. The relative mean fluorescence intensity of CFSE (C) and cell viability (D) were assessed 4 days following stimulation (n = 5, paired t test). (E) Cytokine secretion profiles of JQ1-DMF5 T cells and (–)-JQ1-DMF5 T cells upon stimulation with aAPC/A2 pulsed with the cognate peptide (n = 4, paired t test). (F) DMF5 T cells were cocultured with the melanoma cell line A375 transduced with full-length MART1 (A375/MART1) at the indicated ratio, and the residual cells were analyzed by flow cytometry (n = 5, unpaired t test). (G) The HLA-A2/MART1 T cells generated as shown in A were adoptively transferred into NSG mice subcutaneously injected with 0.5 million A375/MART1 cells. (H) Depiction of the tumor volume until 14 weeks after tumor cell injection (n = 10 each). (I) Kaplan–Meier curve for progression-free survival of the treated mice (n = 10). Representative data from 2 experiments are shown. (J) Frequency of human CD8+ A2/MART1 multimer+ T cells in the peripheral blood following T cell injection. **P < 0.01. NS, not significant.