title: 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.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.forename: Tingxi
authors.initials: T
authors.lastname: Guo
authors.forename: Mark
authors.initials: M
authors.lastname: Anczurowski
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saso
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors