Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors.
Indoleamine 2,3-dioxygenase (IDO) is an interferon (IFN)-gamma-inducible, extrahepatic enzyme that catalyses the initial and rate-limiting step in the degradation of the essential amino acid tryptophan. Elevated tryptophan catabolism mediated by IDO is associated with a wide variety of human cancers and has historically been thought to be a tumoricidal consequence of IFN-gamma exposure. Evidence of a physiological requirement for IDO activity in protecting the allogeneic fetus from rejection by the maternal immune system has stimulated a radical shift in thinking about the role of IDO in cancer. Evidence now suggests that tumours can exploit IDO-mediated peripheral tolerance to promote immune escape. This review summarises key studies that implicate IDO as an important mediator of peripheral immune tolerance as well as the development of a promising new anticancer modality that incorporates the use of IDO inhibitors. The second part focuses on the current state of development of IDO inhibitory compounds as potential pharmaceutical agents.
Muller
Alexander J
AJ
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA. mullera@mlhs.org
Malachowski
William P
WP
Prendergast
George C
GC
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014364:Tryptophan / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan