Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway

Abstract

Chronic inflammation drives the development of many cancers, but a genetic definition of what constitutes 'cancer-associated' inflammation has not been determined. Recently, a mouse genetic study revealed a critical role for the immune escape mediator indoleamine 2,3-dioxygenase (IDO) in supporting inflammatory skin carcinogenesis. IDO is generally regarded as being immunosuppressive; however, there was no discernable difference in generalized inflammatory processes in IDO-null mice under conditions where tumor development was significantly suppressed, implicating IDO as key to establishing the pathogenic state of 'cancer-associated' inflammation. Here we review recent findings and their potential implications to understanding the relationship between immune escape and inflammation in cancer. Briefly, we propose that genetic pathways of immune escape in cancer are synonymous with pathways that define 'cancer-associated' inflammation and that these processes may be identical rather than distinct, as generally presumed, in terms of their genetic definition.

Figure 1

Dual roles of IDO in cancer. IDO is overexpressed in many types of tumor cells where its presence has been associated with poor prognosis. In tumor cells, IDO dysregulation has been linked to inactivation of tumor suppressor gene Bin1, an amphiphysin-like gene that is widely attenuated or misspliced in cancer., In tumor-draining lymph nodes, IDO is upregulated in a regulatory subset of plasmacytoid dendritic cells that has been suggested to inform a positive feedback loop in the activation of T regulatory cells (Tregs), while also blunting their interconversion to Th17 inflammatory cells., IDO activity consumes tryptophan, depriving it from local tissue microenvironments, also generating kynurenine as a product. Both of these processes have been implicated in T cell suppression, including by blunting T effector cell function as well as recruitment of Tregs.

Figure 2

Genetic overlap between immune escape and ‘cancer-associated’ inflammation. A: IDO-deficient mice are resistant to inflammatory skin carcinogenesis. Panels compare several representative IDO^+/+ and IDO^−/− mice from cohorts subjected to a standard classical protocol of two-stage inflammatory skin carcinogenesis that involves a single topical application of DMBA followed by chronic exposure to phorbol ester TPA. Figure derived from Muller et al with permission of the Proceedings of the National Academies of Sciences of the United States of America. B: Traditional versus proposed perspectives on the relationship between ‘cancer-associated’ inflammation and immune escape in the tumor microenvironment. The arrows represent time. Top, The inflammatory tumor microenvironment precedes and engenders immune ‘sculpting’ that supports the development of immune escape. Bottom, The peculiar cancer-supporting elements of the inflammatory tumor microenvironment are genetically identical to the elements that support immune escape.