Indoleamine 2,3-dioxygenase 1 (IDO): A mediator of immunoresistance in adults with brain cancer treated with immunomodulatory therapy

Abstract Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is expressed in > 90% of all adult-resected glioblastoma (GBM) and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted approaches that aim to enhance T-cell infiltration into GBM will in turn result in a compensatory increase of IDO expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO expression is associated with a significant decrease of GBM patient survival and increased immunosuppressive regulatory T cells (CD4+ CD25+ FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn), the depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the anti-GBM immune response. However, our work has challenged this hypothesis, and here we provide a comprehensive update of IDO effects in adults with GBM.