Abstract 2680: A novel pro-tumorigenic role for IDO1 in inflammatory neovascularization

Abstract

Abstract Small molecule inhibitors of the tryptophan catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase 1) have shown early promise in clinical trials as immuno-oncology agents. While the tolerogenic activity of IDO1 has been well established, we have recently identified an additional role for IDO1 in supporting neovascularization at the regulatory interface 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 studies have associated with its anti-angiogenic activity. Conversely, genetic studies in mice have clearly established the tumor-promoting role of IDO1, suggesting that it may act 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 led us to hypothesize that IDO1 might contribute to cancer promotion by countering the anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of IL6. Testing this hypothesis in mouse models of oxygen-induced retinopathy and pulmonary metastasis, we determined that loss of IDO1 did indeed result in reduced neovascularization in conjunction with impaired metastasis outgrowth, effects that were completely reversed by the concurrent elimination of IFNγ. Loss of IL6 was likewise associated with IFNγ-dependent reductions in neovascularization and impaired metastasis outgrowth, as predicted. Having established a novel role for IDO1 in inflammatory neovascularization, current investigations are focused on the underlying molecular and cellular mechanisms involved. At the molecular level, one of the consequences of tryptophan catabolism by IDO1 can be to trigger the ISR (integrated stress response) through activation of the GCN2/CHOP pathway that has previously been linked to the downstream induction of IL6. Thus far, data collected in both the oxygen-induced retinopathy and pulmonary metastasis models are consistent with the ISR being the relevant downstream signaling pathway from IDO1 in this biological context. At the cellular level, we have detected the incorporation of non-endothelial, IDO1-positive cells into the vessels that comprise the neovascular tufts, implicating IDO1 in the process of vasculogenesis. These insights into this unrecognized aspect of IDO1 biology are likely to have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications involving neovascularization as well. Citation Format: Arpita Mondal, Erika Sutanto-Ward, James B. DuHadaway, Arturo Bravo-Nuevo, Sunil Thomas, George C. Prendergast, Alexander J. Muller. A novel pro-tumorigenic role for IDO1 in inflammatory neovascularization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2680. doi:10.1158/1538-7445.AM2017-2680