IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance

Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.

TrendsIDO can be induced in the tumor microenvironment by the spontaneous inflammation and T cell activation associated with many tumors; however, IDO may also be induced reactively, in response to inflammation induced by antitumor immunotherapy.IDO is rapidly induced when mice are challenged with apoptotic cells. Inhibiting or genetically deleting IDO results in loss of self-tolerance to apoptotic cell-associated antigens, and susceptibility to lupus-like autoimmunity.DNA-containing nanoparticles can induce immunosuppressive IDO via a pathway dependent on the STING sensor of cytosolic DNA.When Treg cells are activated in the presence of IDO, they upregulate a highly suppressive phenotype driven by the PTEN lipid phosphatase. In vivo, challenge with apoptotic cells triggers IDO-mediated induction of PTEN-expressing Treg cells.In tumors, IDO induction by apoptotic cells may become relevant as the tumor attempts to inhibit immune responses to dying tumor cells following chemotherapy or immunotherapy.