Abstract 5223: A novel pro-angiogenic role for IDO1 in inflammatory tumor promotion

Chronic inflammation is a major contributing factor in cancer, but, due to the complex multifactorial nature of inflammation, there remains limited understanding of specific pathogenic determinants that might be targeted therapeutically. The tryptophan-catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase) has emerged as an intriguing, pro-tumorigenic regulator of immune function in this regard. Because IDO1 can be elevated in chronic inflammatory states even prior to the initiation of cancer, it may represent one of the earliest determinants directing the immune response towards supporting rather than eliminating tumors. Genetic studies in mice have clearly established the tumor-promoting role of IDO1, but what this actually entails remains uncertain. Here we present evidence to support the novel hypothesis that a principle means by which IDO1 facilitates tumorigenesis is by mitigating immune-based angiostasis. Tumor angiogenesis is characterized by excessive and disorganized blood vessel growth much like that induced by ischemia where immune cells have been shown to be important for limiting neovascularization. Likewise, an anti-angiogenic response may be a factor in tumor immunity. In particular, IFNγ, an inflammatory cytokine, long recognized as a major inducer of IDO1, has been shown to exert angiostatic activity against developing tumors, which was implicated in these studies as the primary mechanism for both CD4 and CD8 T cell dependent tumor rejection. Our recently reported finding that the loss of IDO1 resulted in diminished pulmonary vascularization (Smith, Cancer Discovery 2012) suggested the possibility that IDO1 might be working at cross purposes to limit IFNγ-mediated angiostasis. In this same study IDO1 loss was also associated with the attenuated induction of the pro-angiogenic inflammatory cytokine IL6. To directly investigate the role of IDO1 in pathologic angiogenesis, we have utilized an oxygen-induced retinopathy (OIR) model. As predicted, neovascularization in the OIR model was significantly reduced in Ido1-/- mice. Consistent with the hypothesis that IDO1 supports neovascularization primarily by counteracting the angiostatic activity of IFNγ, neovascularization in double knockout Ifng-/- Ido1-/- mice reverted back to wild type levels. Il6-/- mice, on the other hand, exhibited reduced neovascularization which was likewise reversed by the concurrent elimination of IFNγ. In conjunction with these angiogenesis studies, we have also examined pulmonary metastasis development by 4T1 breast carcinoma isografts. Loss of either IDO1 or IL6 resulted in resistance to pulmonary metastases that, in both cases, was abrogated by the concurrent loss of IFNγ. Taken together, these findings have led us to propose a conceptually novel working hypothesis that, in the context of an inflammatory cytokine milieu, IDO1 plays a key role in supporting tumor angiogenesis. Citation Format: Arpita Mondal, James B. DuHadaway, Erika Sutanto-Ward, Courtney Smith, George C. Prendergast, Arturo Bravo-Nuevo, Alexander J. Muller. A novel pro-angiogenic role for IDO1 in inflammatory tumor promotion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5223. doi:10.1158/1538-7445.AM2015-5223