β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells

Yuan Hong; Indumathi Manoharan; Amol Suryawanshi; Tanmay Majumdar; Melinda L Angus-Hill; Pandelakis A Koni; Balaji Manicassamy; Andrew L Mellor; David H Munn; Santhakumar Manicassamy

doi:10.1158/0008-5472.CAN-14-2377

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β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells

Journal article

Open access

Peer reviewed

β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells

Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Tanmay Majumdar, Melinda L Angus-Hill, Pandelakis A Koni, Balaji Manicassamy, Andrew L Mellor, David H Munn and Santhakumar Manicassamy

Cancer research (Chicago, Ill.), Vol.75(4), pp.656-665

02/15/2015

DOI: 10.1158/0008-5472.CAN-14-2377

PMCID: PMC4333068

PMID: 25568183

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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.

T-Lymphocytes, Regulatory - metabolism

Transcription Factor 4

Signal Transduction

Humans

Dendritic Cells - pathology

Mice, Transgenic

beta Catenin - metabolism

beta Catenin - genetics

T-Lymphocytes, Regulatory - immunology

Vitamin A - metabolism

Tumor Microenvironment - immunology

Animals

Tumor Microenvironment - genetics

CD8-Positive T-Lymphocytes - metabolism

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism

Mice

CD8-Positive T-Lymphocytes - immunology

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - immunology

Dendritic Cells - metabolism

Details

Title: Subtitle: β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells
Creators: Yuan Hong - Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
Indumathi Manoharan - Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
Amol Suryawanshi - Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
Tanmay Majumdar - Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
Melinda L Angus-Hill - Hunstman Cancer Institute, University of Utah, Salt Lake City, UT, USA
Pandelakis A Koni - Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA
Balaji Manicassamy - Department of Microbiology, University of Chicago, Chicago,IL, USA
Andrew L Mellor - Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA
David H Munn - Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA
Santhakumar Manicassamy - Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.75(4), pp.656-665
DOI: 10.1158/0008-5472.CAN-14-2377
PMID: 25568183
PMCID: PMC4333068
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: R01 CA103320 / NCI NIH HHS R01 DK097271 / NIDDK NIH HHS DK097271 / NIDDK NIH HHS R56 AI104875 / NIAID NIH HHS UL1 TR000430 / NCATS NIH HHS AI04875 / NIAID NIH HHS R01 CA096651 / NCI NIH HHS R01 CA112431 / NCI NIH HHS
Language: English
Date published: 02/15/2015
Academic Unit: Microbiology and Immunology
Record Identifier: 9984083283302771

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