title: Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity.
abstract: Forkhead box P3 (Foxp3)(+) T regulatory (T(reg)) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) T(reg) cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) T(reg) cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) T(reg) cells increased T cell receptor-induced apoptosis in T(reg) cells, impaired T(reg) cell suppressive function and peripheral T(reg) cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) T(reg) cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish T(reg) cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.
authors: 1] Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2].
authors: Yujie
authors: Y
authors: Liu
authors: Liqing
authors: L
authors: Wang
authors: Jarrod
authors: J
authors: Predina
authors: Rongxiang
authors: R
authors: Han
authors: Ulf H
authors: UH
authors: Beier
authors: Liang-Chuan S
authors: LC
authors: Wang
authors: Veena
authors: V
authors: Kapoor
authors: Tricia R
authors: TR
authors: Bhatti
authors: Tatiana
authors: T
authors: Akimova
authors: Sunil
authors: S
authors: Singhal
authors: Paul K
authors: PK
authors: Brindle
authors: Philip A
authors: PA
authors: Cole
authors: Steven M
authors: SM
authors: Albelda
authors: Wayne W
authors: WW
authors: Hancock
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D002843:Chromatin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050880:p300-CBP Transcription Factors
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