Immune Escape: Role of Indoleamine 2,3-Dioxygenase in Tumor Tolerance

Summary

Indoleamine 2,3 dioxygenase (IDO) degrades the essential amino acid tryptophan in mammals, catalyzing the initial, rate-limiting step in de novo biosynthesis of the metabolic cofactor nicotinamide adenine dinucleotide (NAD). Broad evidence implicates IDO and the tryptophan catabolic pathway in the generation of immune tolerance to foreign antigens in tissue microenvironments. In particular, recent findings have established that IDO is overexpressed in both tumor cells and antigen-presenting cells in tumor-draining lymph nodes where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the normal physiologic state, IDO is important in creating an environment that limits damage to tissues due to an overactive immune system. However, by fostering immune suppression, IDO can facilitate the survival and growth of tumor cells expressing unique antigens that would otherwise be recognized normally as foreign. In preclinical studies, small-molecule inhibitors of IDO can reverse this mechanism of immune suppression, strongly leveraging the efficacy of classical cancer chemotherapeutic agents to trigger regression of tumors that are otherwise largely resistant to treatment. These results have spurred clinical translation of IDO inhibitors, the first of which entered Phase I human trials in late 2007. In this chapter, we survey work defining IDO as an important mediator of peripheral tolerance, review evidence of IDO dysregulation in cancer cells, and provide an overview of the development of IDO inhibitors as a new immunoregulatory modality to enter clinical trials for cancer treatment.