Novel enzyme IDO2 is the preferred biochemical target of D-1MT which relieves tumor immune suppression and stimulates tumor regression

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Immune escape is a fundamental gateway to cancer. One important mechanism used by many cancers to achieve immune escape is driven by indoleamine 2,3-dioxygenase (IDO), an enzyme widely overexpressed in tumors and/or tumor-draining lymph nodes. Small molecule inhibitors of IDO display anti-tumor activity in preclinical mouse models and clinical evaluation of a lead compound is now underway. One issue related to this lead inhibitor, D-1-methyl-tryptophan (D-1MT), is the breadth of its biochemical specificity for IDO. We have discovered and characterized a new IDO-related enzyme termed IDO2 that is preferentially inhibited by D-1MT compared to IDO. Like IDO, activation of IDO2 catabolizes tryptophan, producing a microenvironmental starvation response that triggers phosphorylation of the translation initiation factor eIF2a and induced translation of LIP, an isoform of the immune regulatory transcription factor NF-IL6. Notably, relieving tryptophan starvation represses this signaling pathway but only when it is activated by IDO, suggesting that IDO2 has a distinct signaling function that may help propagate immune suppression away from a region of relative tryptophan starvation (e.g. from a tumor or lymph node into a pre-metastatic niche). In characterizing the human IDO2 gene we defined two disabling genetic polymorphisms that are widely dispersed in human populations. If IDO2 mediates immune suppression like IDO, this finding may have important implications for understanding individual susceptibility to cancer or cancer progression, based on differences in susceptibility to immune suppression, and also for interpreting clinical responses to D-1MT or other IDO2 inhibitory compounds, based on allelic differences in responding versus non-responding individuals on trial.