Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 44, Pages 17073-17078Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806173105
Keywords
dendritic cells; T cells; TPA; carcinogenesis; tryptophan
Categories
Funding
- National Institutes of Health (NIH) [A163402, CA112431, CA096651, CA109542, CA82222, CA1001123]
- Concern Foundation
- DoD Breast Cancer Research Program [BC044350]
- Lance Armstrong Foundation
- Lankenau Hospital Foundation
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Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN IDCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/lL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO+ pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.
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