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.

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…To test the idea that IDO1 is important for supporting neovascularization outside other possible confounding effects within the tumor microenvironment, studies were conducted in a mouse OIR (oxygen-induced retinopathy) model, a well established, reproducibly quantifiable surrogate system for studying neovascularization (Palmer et al , 2012; Stahl et al , 2012). As predicted, Ido1 −/− mice exhibited a significant reduction in OIR-induced retinal neovascularization relative to their WT counterparts (Mondal et al, 2016). Loss of the related IDO2 isoform had no demonstrable effect on OIR-induced retinal neovascularization, indicating that the effect is specific to IDO1 (Mondal et al, 2016).…”

“…As predicted, Ido1 −/− mice exhibited a significant reduction in OIR-induced retinal neovascularization relative to their WT counterparts (Mondal et al, 2016). Loss of the related IDO2 isoform had no demonstrable effect on OIR-induced retinal neovascularization, indicating that the effect is specific to IDO1 (Mondal et al, 2016). No difference in the normal retinal vascularization that develops under normoxic conditions was observed between Ido1 −/− and WT groups and reduction of the avascular region (Mondal et al, 2016), indicative of normal revascularization, was actually higher in the Ido1 −/− animals indicative of an improvement in normal vascular regrowth occurring in mice lacking IDO1.…”

“…As predicted by this model, pulmonary metastases that developed in Ido1 −/− mice exhibited significantly reduced neovascularization relative to their WT counterparts (Mondal et al , 2016). However, since overall metastatic tumor outgrowth in Ido1 −/− mice was also significantly reduced, it was not clear if the reduction blood vessel formation was a direct effect of IDO1 loss.…”

“…No difference in the normal retinal vascularization that develops under normoxic conditions was observed between Ido1 −/− and WT groups and reduction of the avascular region (Mondal et al, 2016), indicative of normal revascularization, was actually higher in the Ido1 −/− animals indicative of an improvement in normal vascular regrowth occurring in mice lacking IDO1. The reduction in OIR-induced retinal neovascularization observed in mice lacking Ido1 genetically was recapitulated by siRNA-mediated knockdown of Ido1 expression in the retina (Mondal et al, 2016), demonstrating that the effect of IDO1 loss on neovascularization could be elicited both locally and acutely. Likewise, pharmacologic inhibition of IDO1 with the clinical agent epacadostat reduced OIR-induced retinal neovascularization when delivered systemically to neonates (Mondal et al, 2016).…”

“…Loss of the related IDO2 isoform had no demonstrable effect on OIR-induced retinal neovascularization, indicating that the effect is specific to IDO1 (Mondal et al, 2016). No difference in the normal retinal vascularization that develops under normoxic conditions was observed between Ido1 −/− and WT groups and reduction of the avascular region (Mondal et al, 2016), indicative of normal revascularization, was actually higher in the Ido1 −/− animals indicative of an improvement in normal vascular regrowth occurring in mice lacking IDO1. The reduction in OIR-induced retinal neovascularization observed in mice lacking Ido1 genetically was recapitulated by siRNA-mediated knockdown of Ido1 expression in the retina (Mondal et al, 2016), demonstrating that the effect of IDO1 loss on neovascularization could be elicited both locally and acutely.…”