Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.

Oncogenic activation of the proto-oncogene c-abl in human leukemias occurs as a result of the addition of exons from the gene bcr and truncation of the first abl exon. Analysis of tyrosine kinase activity and quantitative measurement of transformation potency in a single-step assay indicate that variation in bcr exon contribution results in a functional difference between p210bcr-abl and p185bcr-abl proteins. Thus, foreign upstream sequences are important in the deregulation of the kinase activity of the abl product, and the extent of deregulation correlates with the pathological effects of the bcr-abl proteins.

Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyltryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the D isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block hostmediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens. [Cancer Res 2007;67(2):792-801]

Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, D-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2A, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases. [Cancer Res 2007;67(15):7082-7]