Innovative drugs targeting IDO1 functions in neoplasia

Date

05 Mar 2018

Session

Novel immuno targets

Presenters

Francesca Fallarino

Citation

Annals of Oncology (2018) 29 (suppl_3): iii1-iii6. 10.1093/annonc/mdy046

Authors

F. Fallarino

Author affiliations

  • -, Azienda Ospedaliera di Perugia S. Maria della Misericordia, 06132 - Perugia/IT
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Resources

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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.

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