title: Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.
abstract: Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses. Rather, IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inflammatory tissue microenvironment even in the absence of cancer. IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter. In the context of inflammatory carcinogenesis where IDO was critical to tumor development, the most important source of IDO was radiation-resistant non-hematopoietic cells, consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism. Taken together, our results identify IDO as an integral component of 'cancer-associated' inflammation that tilts the immune system toward tumor support. More generally, they promote the concept that mediators of immune escape and cancer-associated inflammation may be genetically synonymous.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Chang
authors.forename: Arivudinambi
authors.initials: A
authors.lastname: Ramalingam
authors.forename: Erika
authors.initials: E
authors.lastname: Sutanto-Ward
authors.forename: Janette
authors.initials: J
authors.lastname: Boulden
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Soler
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D002273:Carcinogens / Q000633:toxicity; D004357:Drug Synergism; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D012878:Skin Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019139:Tumor Escape; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020298:U937 Cells; D014916:Whole-Body Irradiation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D002273:Carcinogens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate