Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion
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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.
KeywordsIndoleamine 2,3-dioxygenase Immunosuppression Carcinogenesis
This work was supported by grants from the DoD Breast Cancer Research Program (A.J.M., G.C.P.), Pennsylvania Department of Health CURE/Tobacco Settlement Award (A.J.M.) and NIH grants CA82222 (G.C.P.), CA109542 (G.C.P.), and CA070739 (S.K.G.). Additional support was also provided by New Link Genetics Corporation, Dan Green Foundation, Lankenau Hospital Foundation, and the Main Line Health System (G.C.P.). A conflict of interest is declared by G.C.P., A.J.M., and J.B.D. who have intellectual property rights and financial interests in New Link Genetics Corporation which is developing IDO inhibitors for treatment of cancer and other diseases.
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