title: β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells.
abstract: Tumors actively suppress antitumor immunity, creating formidable barriers to successful cancer immunotherapy. The molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that dendritic cells (DC) in the tumor microenvironment acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives regulatory T-cell responses and immune tolerance. Tolerogenic responses were dependent on induction of vitamin A-metabolizing enzymes via the β-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of β-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A-metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Indumathi
authors.initials: I
authors.lastname: Manoharan
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Tanmay
authors.initials: T
authors.lastname: Majumdar
authors.affiliation: Hunstman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Angus-Hill
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.|Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.affiliation: Department of Microbiology, University of Chicago, Chicago,IL, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.|Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.|Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.|Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000073940:Transcription Factor 4; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D014801:Vitamin A / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051176:beta Catenin; D014801:Vitamin A