title: BPTF Depletion Enhances T-cell-Mediated Antitumor Immunity.
abstract: Genetic studies in fruit flies have implicated the chromatin remodeling complex nucleosome remodeling factor (NURF) in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. We found that both CD8+and CD4+T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8+T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8+T cells cocultured with BPTF-silenced cells. Similar effects were not produced with T-cell receptor transgenic CD8+T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8+T-cell clones from mice bearing BPTF-silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2 The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T-cell cytotoxicity, and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity. Cancer Res; 76(21); 6183-92. ©2016 AACR.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Mayes
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Suehyb G
authors.initials: SG
authors.lastname: Alkhatib
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Kristen
authors.initials: K
authors.lastname: Peterson
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Aiman
authors.initials: A
authors.lastname: Alhazmi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Vivian
authors.initials: V
authors.lastname: Chan
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Tana
authors.initials: T
authors.lastname: Blevins
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mark
authors.initials: M
authors.lastname: Roberts
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dumur
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. joseph.landry@vcuhealth.org.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Landry
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D034961:Antigens, Nuclear / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009707:Nucleosomes / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D009419:Nerve Tissue Proteins; D009707:Nucleosomes; D014157:Transcription Factors; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins