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 language | English (US) |
---|---|
Pages (from-to) | 1460-1468 |
Number of pages | 9 |
Journal | OncoImmunology |
Volume | 1 |
Issue number | 9 |
DOIs | |
State | Published - 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