Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase.

Abstract

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 DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-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.

• Authors: Alexander J Muller, Madhav D Sharma, Phillip R Chandler, James B Duhadaway, Mary E Everhart, Burles A Johnson 3rd, David J Kahler, Jeanene Pihkala, Alejandro Peralta Soler, David H Munn, George C Prendergast, Andrew L Mellor
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 44 Pg. 17073-8 (Nov 04 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18952840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Dendritic Cells (cytology, enzymology, immunology)
• Dermatitis, Contact (enzymology, immunology, pathology)
• Disease Progression
• Immune Tolerance (immunology)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics, metabolism)
• Lymph Nodes (enzymology, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Papilloma (immunology, pathology)
• Signal Transduction (immunology)
• Skin Neoplasms (immunology, pathology)
• T-Lymphocytes (immunology, metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)