title: IDO1 is an Integral Mediator of Inflammatory Neovascularization.
abstract: The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFNγ. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFNγ abrogated. This insight into IDO1's involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well.
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States; Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 W. Queen Ln., Philadelphia, PA 19129, United States.
authors.forename: Arpita
authors.initials: A
authors.lastname: Mondal
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Smith
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States.
authors.forename: Erika
authors.initials: E
authors.lastname: Sutanto-Ward
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States; Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., Philadelphia, PA 19107, United States.
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States.
authors.forename: Arturo
authors.initials: A
authors.lastname: Bravo-Nuevo
authors.affiliation: Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, United States; Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., Philadelphia, PA 19107, United States. Electronic address: muller@limr.org.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators
keywords: Angiogenesis; Indoleamine 2,3-dioxygenase; Inflammation; Interferon-gamma; Interleukin 6; Lung metastasis; Oxygen-induced retinopathy; Tryptophan