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Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer

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Abstract

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.

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Abbreviations

1MT:

1-Methyl-tryptophan

AhR:

Aryl hydrocarbon receptor (kynurenine receptor)

CCL-2:

Myeloid attraction cytokine (also known as MCP-1) which binds to receptors CCR2 and CCR4 and causes basophils and mast cells to release their granules

eIF-2α:

Master regulatory eukaryotic translation initiation factor

Gcn2:

Starvation-induced kinase that phosporylates and suppresses eIF-2α

GLK1:

A kinase also known as MAP4K3 that responds to amino acid sufficiency by activating mTORC1

IDO:

Indoleamine 2,3-dioxygenase (also known as IDO1)

IDO2:

Distinct gene encoding an IDO-related enyzme with weaker tryptophan catabolic activity

IFN-γ:

Interferon-γ

MDSC:

Myeloid-derived suppressor cells

INCB024360:

A specific small-molecule inhibitor of IDO1 enzymatic activity in clinical trials

Indoximod:

D racemer of 1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor in clinical trials that relieves IDO-mediated suppression of the mTORC1 pathway (also known as NLG8189)

mTORC1:

Mammalian target of rapamycin complex-1, a master cell growth regulatory kinase

NLG919:

A specific small-molecule inhibitor of IDO1 enzymatic activity in clinical trials

NK:

Natural killer immune cells

PGE-2:

Pro-inflammatory prostaglandin produced by activation of COX-2 which may rely on IDO function for its pro-cancerous activity

PKC-θ:

Protein kinase C variant that phosphorylates and limits the function of the T cell receptor

TDLN:

Tumor-draining lymph node

TLR:

Toll-like receptor (infection/inflammation-associated PAMP receptor)

TGF-β:

Transforming growth factor-β

TPA:

12-O-tetradecanoylphorbol-13-acetate (pro-inflammatory chemical also known as PMA)

Treg:

T regulatory cells

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Acknowledgments

Work in the authors’ laboratories has been supported by grants from the NIH, Department of Defense Breast and Lung Cancer Research Programs, Susan G. Komen for the Cure and the W.W. Smith Trust with additional support from NewLink Genetics Corporation, Sharpe-Strumia Foundation, Dan Green Foundation, Lankenau Medical Center Foundation and the Main Line Health System. C. Smith was the recipient of a Postdoctoral Fellowship through the US Department of Defense Breast Cancer Research Program.

Conflict of interest

G.C. Prendergast, R. Metz and A.J. Muller state a conflict of interest as shareholders and G.C. Prendergast also a grant recipient and a member of the scientific advisory board for New Link Genetics Corporation, a biopharmaceutical company that has licensed IDO intellectual property for clinical development from the Lankenau Institute of Medical Research, as described in U.S. Patents Nos. 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454 and 8586636. The other authors state no conflict of interest.

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Authors and Affiliations

  1. Lankenau Institute for Medical Research (LIMR), 100 Lancaster Avenue, Wynnewood, PA, 19096, USA

    George C. Prendergast, Courtney Smith, Sunil Thomas, Laura Mandik-Nayak, Lisa Laury-Kleintop & Alexander J. Muller

  2. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    George C. Prendergast & Alexander J. Muller

  3. New Link Genetics Corporation, Ames, IA, USA

    Richard Metz

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  1. George C. Prendergast
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  2. Courtney Smith
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  3. Sunil Thomas
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  4. Laura Mandik-Nayak
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  5. Lisa Laury-Kleintop
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  6. Richard Metz
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  7. Alexander J. Muller
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Correspondence to George C. Prendergast.

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This paper is a Focussed Research Review based on a presentation given at the Eleventh Annual Meeting of the Association for Cancer Immunotherapy (CIMT), held in Mainz, Germany, 14th-16th May, 2013. It is part of a CII series of Focussed Research Reviews and meeting report.

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Prendergast, G.C., Smith, C., Thomas, S. et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother 63, 721–735 (2014). https://doi.org/10.1007/s00262-014-1549-4

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