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

Alexander J. Muller, Madhav D. Sharma, Phillip R. Chandler, James B. DuHadaway, Mary E. Everhart, Burles A. Johnson, David J. Kahler, Jeanene Pihkala, Alejandro Peralta Soler, David H. Munn, George C. Prendergast, Andrew L. Mellor

Research output: Contribution to journalArticle

166 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)17073-17078
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number44
DOIs
StatePublished - Nov 4 2008

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Tetradecanoylphorbol Acetate
Dendritic Cells
Inflammation
Neoplasms
T-Lymphocytes
9,10-Dimethyl-1,2-benzanthracene
Skin
Interleukin-1 Receptors
Papilloma
Immunosuppressive Agents
Carcinogens
Carcinogenesis
Phosphotransferases
Lymph Nodes
Phenotype
Amino Acids

Keywords

  • Carcinogenesis
  • Dendritic cells
  • T cells
  • TPA
  • Tryptophan

ASJC Scopus subject areas

  • General

Cite this

Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. / Muller, Alexander J.; Sharma, Madhav D.; Chandler, Phillip R.; DuHadaway, James B.; Everhart, Mary E.; Johnson, Burles A.; Kahler, David J.; Pihkala, Jeanene; Soler, Alejandro Peralta; Munn, David H.; Prendergast, George C.; Mellor, Andrew L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 44, 04.11.2008, p. 17073-17078.

Research output: Contribution to journalArticle

Muller, AJ, Sharma, MD, Chandler, PR, DuHadaway, JB, Everhart, ME, Johnson, BA, Kahler, DJ, Pihkala, J, Soler, AP, Munn, DH, Prendergast, GC & Mellor, AL 2008, 'Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 44, pp. 17073-17078. https://doi.org/10.1073/pnas.0806173105
Muller, Alexander J. ; Sharma, Madhav D. ; Chandler, Phillip R. ; DuHadaway, James B. ; Everhart, Mary E. ; Johnson, Burles A. ; Kahler, David J. ; Pihkala, Jeanene ; Soler, Alejandro Peralta ; Munn, David H. ; Prendergast, George C. ; Mellor, Andrew L. / Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 44. pp. 17073-17078.
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AU - Sharma, Madhav D.

AU - Chandler, Phillip R.

AU - DuHadaway, James B.

AU - Everhart, Mary E.

AU - Johnson, Burles A.

AU - Kahler, David J.

AU - Pihkala, Jeanene

AU - Soler, Alejandro Peralta

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