title: IDO inhibits a tryptophan sufficiency signal that stimulates mTOR:  A novel IDO effector pathway targeted by D-1-methyl-tryptophan.
abstract: Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-cell tolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integrated stress response kinase GCN2, a sensor of uncharged tRNA that is activated by amino acid deprivation, is recognized as an important effector of the IDO pathway. However, in a mouse model of inflammatory carcinogenesis, ablation of Gcn2 did not promote resistance against tumor development like the absence of IDO does, implying the existence of additional cancer-relevant pathways that operate downstream of IDO. Addressing this gap in knowledge, we report that the IDO-mediated catabolism of tryptophan also inhibits the immunoregulatory kinases mTOR and PKC-Θ, along with the induction of autophagy. These effects were relieved specifically by tryptophan but also by the experimental agent 1-methyl-D-tryptophan (D-1MT, also known as NLG8189), the latter of which reversed the inhibitory signals generated by IDO with higher potency. Taken together, our results implicate mTOR and PKC-Θ in IDO-mediated immunosuppressive signaling, and they provide timely insights into the unique mechanism of action of D-1MT as compared with traditional biochemical inhibitors of IDO. These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO, IDO2 or TDO). Moreover, they define mTOR and PKC-Θ as candidate pharmacodynamic markers for D-1MT responses in patients recruited to ongoing phase IB/II cancer trials, addressing a current clinical need.
authors.affiliation: New Link Genetics Corporation; Ames, IA USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Metz
authors.forename: Sonja
authors.initials: S
authors.lastname: Rust
authors.forename: James B
authors.initials: JB
authors.lastname: Duhadaway
authors.forename: Mario R
authors.initials: MR
authors.lastname: Mautino
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Vahanian
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Link
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast