Journal
CANCER RESEARCH
Volume 75, Issue 4, Pages 656-665Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2377
Keywords
-
Categories
Funding
- NIH [DK097271, AI04875]
- GRU Cancer Center Seed Grant
Ask authors/readers for more resources
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 beta-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of beta-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A-metabolizing enzymes or the beta-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, beta-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. (C)2015 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available