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Erschienen in:

01.07.2014 | Focussed Research Review

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

verfasst von: George C. Prendergast, Courtney Smith, Sunil Thomas, Laura Mandik-Nayak, Lisa Laury-Kleintop, Richard Metz, Alexander J. Muller

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2014

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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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Titel: Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer
verfasst von: George C. Prendergast
Courtney Smith
Sunil Thomas
Laura Mandik-Nayak
Lisa Laury-Kleintop
Richard Metz
Alexander J. Muller
Publikationsdatum: 01.07.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2014
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1549-4

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Springer Medizin

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

Abstract

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