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

147 Citations (Scopus)

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

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Tryptophan
Neoplasms
Phosphotransferases
Autophagy
Immunosuppressive Agents
Transfer RNA
tryptophan methyl ester
Carcinogenesis
Inflammation
Amino Acids
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

Cite this

IDO inhibits a tryptophan sufficiency signal that stimulates mTOR : A novel IDO effector pathway targeted by D-1-methyl-tryptophan. / Metz, Richard; Rust, Sonja; DuHadaway, James B.; Mautino, Mario R.; Munn, David H; Vahanian, Nicholas N.; Link, Charles J.; Prendergast, George C.

In: OncoImmunology, Vol. 1, No. 9, 01.12.2012, p. 1460-1468.

Research output: Contribution to journalArticle

Metz, R, Rust, S, DuHadaway, JB, Mautino, MR, Munn, DH, Vahanian, NN, Link, CJ & Prendergast, GC 2012, 'IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan', OncoImmunology, vol. 1, no. 9, pp. 1460-1468. https://doi.org/10.4161/onci.21716
Metz, Richard ; Rust, Sonja ; DuHadaway, James B. ; Mautino, Mario R. ; Munn, David H ; Vahanian, Nicholas N. ; Link, Charles J. ; Prendergast, George C. / IDO inhibits a tryptophan sufficiency signal that stimulates mTOR : A novel IDO effector pathway targeted by D-1-methyl-tryptophan. In: OncoImmunology. 2012 ; Vol. 1, No. 9. pp. 1460-1468.
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