Indoleamine 2,3-Dioxygenase Amino Acid Metabolism and Tumour-Associated Macrophages: Regulation in Cancer-Associated Inflammation and Immune Escape

Abstract

Indoleamine 2,3-dioxygenases (IDO) enzymes that catabolize tryptophan are expressed in tumor, stromal, and immune cells in the tumor microenvironment, including in monocytic cells such as macrophages (TAMs). Recent mouse genetic studies define a crucial role for IDO in supporting inflammatory carcinogenesis. Key gaps remain in elucidating the immunoregulatory pathways that modify progression versus dormancy in early stage tumors, an important clinical concern. Within the tumor microenvironment, chronic inflammation and immune escape are critical contributors to progression. However, there is still limited knowledge about the molecular mechanisms which underlie cancer-associated inflammation and immune escape in cancer. Both the IDO1 and IDO2 enzymes that catabolize tryptophan have been implicated in immune escape (pathogenic immune tolerance). Contributions from different parts of the tumor microenvironment have yet to be fully defined, but an important implication of these recent studies is that pathways of immune escape and pathogenic inflammation in cancer may be genetically synonymous. IDO enzymes are generally regarded as being immunosuppressive, however, emerging evidence suggests that this view is too narrow and that IDO enzymes may function more broadly to modify or ‘flavor’ the nature of an inflammatory microenvironment, rendering it supportive to tumor progression. In this review, we summarize work on IDO in immune escape and pathogenic inflammation in cancer, discussing potential roles for IDO pathways and other amino acid catabolism pathways in TAMs and other immune cells that may contribute to shaping tissue microenvironments that nurture the development and progression of malignancy.