Abstract
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme that mediates immune tolerance in a variety of physiological settings such as pregnancy and pathophysiological settings such as cancer. IDO is widely elevated in human tumors and tumor-draining lymph nodes (TDLNs) where it facilitates immune escape. Mouse genetic studies indicate that IDO is controlled by tumor suppressor gene Bin1, which is often attenuated in human cancers, and that Bin1 and IDO have opposing roles in inflammatory epithelial carcinogenesis. Notably, IDO is essential to support the development of a regulatory plasmacytoid dendritic cell population that supports Treg development and that is essential to support malignant growth. Consistent with a genetic requirement of IDO for carcinogenesis, we have defined several structural classes of small molecule inhibitors of IDO that in a variety of mouse models will stanch malignant growth and cooperate with classical chemotherapy to trigger durable tumor regressions. In studying the effects of D-1MT, a clinical lead inhibitor presently in Phase I trials, we found that this compound preferentially targets IDO2, a novel IDO-related enzyme. Recent studies argue that IDO2 acts downstream of IDO in immune control. In particular, IDO2 activity appears to rely upon a posttranslational mechanism that is switched on by IDO-mediated tryptophan catabolism. D-1MT is genetically reliant upon IDO consistent with the notion of an IDO1 > IDO2 pathway. Inactivating polymorphisms found in the IDO2 gene are occur commonly in human populations, hinting at variations in susceptibility to tumoral immune control and/or D-1MT response via the IDO-IDO2 pathway. IDO2 genotyping might impact recruitment of patients or interpreting their responses during ongoing clinical evaluations of D-1MT.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5069.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
