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

Richard Metz, Sonja Rust, James B. DuHadaway, Mario R. Mautino, David H. Munn, Nicholas N. Vahanian, Charles J. Link, George C. Prendergast

Research output: Contribution to journalArticle

179 Scopus citations

Abstract

Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-celltolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integratedstress 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. Theseeffects 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 byIDO 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.

Original languageEnglish (US)
Pages (from-to)1460-1468
Number of pages9
JournalOncoImmunology
Volume1
Issue number9
DOIs
StatePublished - Dec 1 2012

Keywords

  • Amino acid starvation
  • Autophagy
  • IDO
  • IDO2
  • Immunomodulation
  • MTOR
  • PKC-θ
  • S6K
  • Stress signaling
  • TDO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Metz, R., Rust, S., DuHadaway, J. B., Mautino, M. R., Munn, D. H., Vahanian, N. N., Link, C. J., & Prendergast, G. C. (2012). IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. OncoImmunology, 1(9), 1460-1468. https://doi.org/10.4161/onci.21716