Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions.
We tested more than 500 small compounds, selected by molecular moleculing and IDO1 binding properties by MicroScale Thermophoresis, in a cellular assay with tumor cells transfected with wild-type IDO1 or IDO1 mutants. Interesting compounds were further evaluated in dendritic cells to establish their capacity to modulate IDO1 signaling activity and immunosuppressive properties.
Besides identifying several new potential drugs inhibiting IDO1 catalytic activity, we identified one compound that was clearly capable of potentiating IDO1 signaling activity and few compounds that weakly inhibited the same IDO1 function.
Although our studies have not led to the identification of a potent negative modulator of IDO1 signaling activity yet, the identification of a positive modulator does indicate that the modulation of IDO1 signaling is feasible and therefore further studies may lead to the generation of innvoative drugs, i.e., IDO1 signaling inhibitors, which could be of possible valuable therapeutic use in the immuno-oncology field.
University of Perugia, Perugia, Italy
European Research Council
All authors have declared no conflicts of interest.