Abstract 1474: IDO1 signaling supports inflammatory neovascularization

Abstract

Abstract We have identified a distinct role for the immunoregulatory, tryptophan-catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase) in supporting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ (interferon γ) and IL6 (interleukin 6). IFNγ is a primary inducer of IDO1, but is also a key mediator of immune-based tumor suppression, which some studies have associated with its anti-angiogenic activity. Conversely, genetic studies in mice have clearly established a tumor-promoting role for IDO1, suggesting that it may interact with IFNγ in a negative feedback capacity. Targeted disruption of the Ido1 gene in mice resulted in enhanced resistance to lung tumor and metastasis development. This corresponded with attenuated induction of the pro-angiogenic cytokine IL6, which, when provided through ectopic expression, was able to restore pulmonary metastasis susceptibility to Ido1-/- mice. These initial findings suggested that IDO1 might contribute to cancer promotion by countering the anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of IL6. Consistent with this hypothesis, mice lacking either IDO1 or IL6 exhibited pulmonary metastasis resistance that was dependent on IFNγ and coupled with reduced tumor neovascularization. Neovascularization in a mouse oxygen-induced retinopathy model was likewise affected by IDO1 or IL6 loss, separating this process from the contextual complexity of the tumor microenvironment. Investigation into the cellular and molecular basis for the observed biology revealed that, within the heterogeneous expanse of Gr1+ MDSCs (myeloid-derived suppressor cells), the ability to independently elicit neovascularization in vivo was restricted to a highly autofluorescent population of CD11blo cells. This included a discrete, IDO1-expressing subpopulation, designated IDVCs (IDO1-dependent vascularizing cells), that, in an IDO1-dependent fashion, dominantly determined whether neovascularization was sustained. Mechanistically, the induction of IDO1 in IDVCs was found to provide a negative feedback constraint on the anti-angiogenic effect of host IFNγ through GCN2 (general control nonderepressible 2)-mediated activation of the integrated stress response and potentiation of IL6 production within these cells. These findings reveal fundamental molecular and cellular insights into how IDO1 interfaces with the inflammatory milieu to support neovascularization. Citation Format: Souvik Dey, Arpita Mondal, James B. DuHadaway, Erika Sutanto-Ward, Lisa Laury-Kleintop, Sunil Thomas, George C. Prendergast, Laura Mandik-Nayak, Alexander J. Muller. IDO1 signaling supports inflammatory neovascularization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1474.