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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-?, 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-? 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-? as candidate pharmacodynamic markers for D-1MT responses in patients recruited to ongoing phase IB/II cancer trials, addressing a current clinical need.

SUBMITTER: Metz R 

PROVIDER: S-EPMC3525601 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan.

Metz Richard R   Rust Sonja S   Duhadaway James B JB   Mautino Mario R MR   Munn David H DH   Vahanian Nicholas N NN   Link Charles J CJ   Prendergast George C GC  

Oncoimmunology 20121201 9


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 abse  ...[more]

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