Abstract 3665: IDO1 is an integrative determinant of tumor-promoting, pathogenic inflammation

Abstract

Abstract The tryptophan-catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase 1) has been implicated as a mediator of immune tolerance in the reproductively essential process of shielding the ‘foreign’ fetus from maternal immunity. By extrapolation, we and others hypothesized that tumors might elevate IDO1 under selective pressure by the immune system. Our finding that loss of the Bin1 tumor suppressor gene potentiates the superinduction of IDO1 provided the first discreet example of a molecular pathway through which this immune escape process can occur. However, the involvement of IDO1 in tumorigenesis has turned out to be far more complex. Tumors that inherently lack IDO1 expression have been demonstrated to induce IDO1 expression in antigen presenting cells of the host, providing an alternative mechanism for immune escape. We have also found from studies in the classical DMBA/TPA skin carcinogenesis model that IDO1 can be induced by the inflammatory tumor-promoting process itself independent of the presence of an initiated tumor. Thus, IDO1 can be a factor in tumor promotion throughout the entire immunoediting process. With the rapid pace of development of IDO inhibitors, which are currently being evaluated in clinical trials, we are interested in determining whether mouse tumor models might provide additional insight into the optimal therapeutic application of these agents based on the underlying biology. In current studies, we have found that IDO1-nullizygous mice are resistant to both KRAS-induced lung adenocarcinomas and pulmonary breast carcinoma metastases. Micro-computed tomographic imaging confirmed that lung tumor burden was correspondingly lower in IDO1-nullizygous mice. Surprisingly, this analysis also revealed a significantly reduced pulmonary blood vessel density in IDO1-nullizygous mice. Elevation of the inflammatory cytokine IL6 (interleukin 6) was greatly attenuated in conjunction with the loss of IDO1, consistent with in vitro evidence that IDO1 potentiates IL6 production. MDSCs (myeloid derived suppressor cells) from IDO1-nullizygous animals exhibited reduced T cell suppressive activity that could be rescued by IL6. IL6 could likewise reverse the pulmonary metastasis resistance exhibited by IDO1-nullizygous mice. Together, our findings provide support for the emerging concept of IDO1 as a prototypical, integrative immune modifier that bridges inflammation, vascularization and immune escape to foster the establishment of a pathogenic, tumor-promoting environment. Citation Format: Alexander J. Muller, Courtney Smith, Mee Young Chang, James DuHadaway, Arpita Mondal, Hollie Flick, Katherine Parker, Daniel Beury, Suzanne Ostrand-Rosenberg, George C. Prendergast. IDO1 is an integrative determinant of tumor-promoting, pathogenic inflammation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2014-3665