Oncotarget

Research Papers:

Indoximod opposes the immunosuppressive effects mediated by IDO and TDO via modulation of AhR function and activation of mTORC1

Erik L. Brincks _, James Adams, Lifu Wang, Benjamin Turner, Agnieszka Marcinowicz, Jiyuan Ke, Michael Essmann, Lucía M. Mautino, Clarissa Van Allen, Sanjeev Kumar, Nicholas Vahanian, Charles Link and Mario R. Mautino

PDF  |  Full Text  |  Supplementary Files  |  How to cite  |  Press Release  |  Order a Reprint

Oncotarget. 2020; 11:2438-2461. https://doi.org/10.18632/oncotarget.27646

Metrics: PDF 18 views  |   Full Text 55 views  |   ?  


Abstract

Erik L. Brincks1,2, James Adams1, Lifu Wang1, Benjamin Turner1, Agnieszka Marcinowicz1, Jiyuan Ke1, Michael Essmann1, Lucía M. Mautino1, Clarissa Van Allen1, Sanjeev Kumar1, Nicholas Vahanian1, Charles Link1 and Mario R. Mautino1

1 NewLink Genetics Corporation, Ames, IA, USA

2 Lumos Pharma, Inc., Ames, IA, USA

Correspondence to:

Erik L. Brincks,email: ebrincks@lumos-pharma.com

Keywords: indoximod; IDO; TDO; AhR; mTORC1

Received: April 13, 2020     Accepted: June 01, 2020     Published: June 23, 2020

ABSTRACT

Indoximod has shaped our understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Previous studies demonstrated that indoximod creates a tryptophan (Trp) sufficiency signal that reactivates mTOR in the context of low Trp concentrations, thus opposing the effects caused by IDO1. Here we extend the understanding of indoximod’s mechanism of action by showing that it has pleiotropic effects on immune regulation. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor (AhR), which controls transcription of several genes in response to different ligands including kynurenine (Kyn). Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. These indoximod-driven effects on CD8+ and CD4+ T cells were independent from the activity of IDO/TDO and from the presence of exogenous Kyn, though they do oppose the effects of Kyn produced by these Trp catabolizing enzymes. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the AhR. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 27646