IMPS-39IDO1: MORE THAN JUST AN ENZYME IN MALIGNANT GLIOMA

Abstract

The upregulation of indoleamine 2,3 dioxygenase 1 (IDO1) in glioblastoma (GBM) is associated with significantly decreased survival in patients. Coincidently, a GL261 glioma model genetically deficient (ie. knocked down) for tumor-derived IDO1 fails to accumulate significant levels of immunosuppressive regulatory T cells (Treg; CD4+CD25+FoxP3+), which is commensurate with a substantial survival advantage. Paradoxically, mice bearing malignant glioma and administered L1-MT, an enzymatic inhibitor of IDO1, fail to demonstrate any survival advantage. To further understand the role of IDO1 in brain tumors, my laboratory recently crossed the tamoxifen-inducible model of malignant glioma [tGBM; GFAP(ERT2)Cre+/-;p53fl/fl;Rbfl/fl;pTENfl/fl] (Chow et al., 2011; Cancer Cell) with IDO1fl/fl or IDO1−/- mice to conditionally- or globally-delete IDO1, respectively. In contrast to previous findings, the loss of tumor-derived IDO1 did not increase overall survival, with a median of 153.5 ±7.0-, 136 ±4.3- and 144.5 ±5.9-days post-tamoxifen administration for tGBM-IDO1wt/wt, tGBM-IDO1fl/fl and tGBM-IDO1−/- mice, respectively (11-12 mice/group). Concordantly, Treg accumulated in the tGBM brain tumors, regardless of IDO1 status. Unexpectedly, when tGBM-WT and tGBM-IDO1−/- tumors were isolated, followed by intracranial re-implantation (ic.) into immunocompetent syngeneic hosts, mice bearing IDO1−/- glioma survived 45.4 ±4.3 days post-ic., which was significantly longer than mice bearing WT glioma at 30.4 ±2.6 days post-ic (P = 0.0069; n = 5-9/group). These data, in combination with recent work from my laboratory demonstrating that, IDO1 in glioma cells fail to metabolize tryptophan into kynurenine, led us to search for a novel and/or contextual function. Here, we present bioinformatics analysis, Western blotting of nuclear and cytoplasmic extracts, as well as immunofluorescence showing that, IDO1 is detectable in the nucleus of glioma cells, in vivo. Strikingly, Chip-Seq. analysis confirms that IDO1 binds to- and enriches-specific DNA sites. This work identifies a novel and previously unappreciated role for IDO1-mediated immune-evasion and introduces new targets for therapeutic discovery and intervention against malignant brain tumors.