Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 9, Pages 3479-3494Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI86437
Keywords
-
Categories
Funding
- NIH [R01 CA148673]
- Ontario Institute for Cancer Research Clinical Investigator Award [IA-039]
- Japan Society for the Promotion of Science Postdoctoral Fellowship
- Princess Margaret Cancer Foundation
- Guglietti Fellowship Award
- Frederick Banting and Charles Best Canada Graduate Scholarship
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD) [115766]
- Janssen
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Merck Co.
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available