IDO1 is an Integral Mediator of Inflammatory Neovascularization

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. •As a result of IDO1 loss, NV (neovascularization) is reduced in pulmonary metastasis and oxygen-induced retinopathy models•IFNγ, an upstream inflammatory cytokine, is required for the reduced NV and pulmonary metastasis outgrowth due to IDO1 loss•Loss of IL6, a downstream inflammatory cytokine, has similar IFNg-dependent effects on NV and metastasis as loss of IDO1 The tryptophan-catabolizing enzyme IDO1 has garnered clinical attention as a potential immuno-oncology target. In this report, Mondal, et al. demonstrate an additional role for IDO1 in supporting neovascularization – the development of new blood vessels that contributes to cancer and other diseases. IDO1's involvement in neovascularization is confirmed in a retinopathy model and correlated with tumor outgrowth in a pulmonary metastasis model. The impact of IDO1 loss on neovascularization is shown to be dependent on IFNγ and mimicked by the loss of IL6, two inflammatory cytokines that control and are controlled by IDO1 respectively, advancing the concept of IDO1 as an orchestrator of tumo