Abstract 5213: Understanding how IDVCs (IDO1-dependent vascularizing cells) respond to and shape the inflammatory milieu to promote neovascularization
Authors: Shih-Chun Shen, James B. DuHadaway, Erika Sutanto-Ward, George C. Prendergast, Alexander J. Muller
Journal: Cancer Research (2025)

Abstract Inflammation and angiogenesis are considered fundamental processes within the TME to the extent that they have been designated “hallmarks of cancer”. In studying tumor development in the lungs, we discovered that the tryptophan catabolizing enzyme IDO1 interconnects these two processes by realigning local inflammation to promote neovascularization. Specifically, the inflammatory cytokine IFNγ elicits neovascular regression, however, it is also a primary inducer of IDO1, which acts in a negative feedback capacity to counter the anti-neovascular activity of IFNγ through the GCN2/ISR dependent induction of an opposing inflammatory cytokine IL6. At the heart of these studies has been the identification of a unique, IDO1-expressing myeloid cell population designated IDVCs (IDO1-dependent vascularizing cells) based on their functional capacity to support neovascularization in an IDO1 dependent manner. A powerful tool used in these studies to analyze the biological activity of isolated IDVCs is the Matrigel plug assay in which FACS sorted cells are incorporated into a subcutaneously implanted Matrigel plug, which is subsequently evaluated by confocal microscopy for blood vessel density. An actionable breakthrough in addressing the fundamental question of how the inflammatory cytokines IFNγ and IL6 respectively promote and mitigate neovascular regression has emerged from subsequent studies that have identified the NOS2 enzyme, previously implicated in facilitating the IFNγ mediated anti-tumor response, as playing a downstream effector role in driving neovascular regression. Based on aggregate evidence obtained from analyzing 4T1 metastatic tumors and Matrigel plugs, we have constructed a basic conceptual framework for how inflammatory neovascularization is orchestrated by IDVCs. The likely source of IFNγ appears to be NK cells, though how they are recruited and activated by IDVCs remains to be determined. In response, the IFNγ inducible chemokine CXCL10, also apparently produced by IDVCs and signaling through its receptor CXCR3, serves a bridging role leading to the induction of NOS2. However, through induction of IDO1 in IDVCs, IFNγ also drives IL6 trans-signaling, which counteracts the CXCL10/NOS2 neovascular regression pathway. Underlying all this, the initial process of establishing the neovasculature, which is also orchestrated by IDVCs but independently of IDO1, appears to involve vasculogenesis (vessels formed by recruited endothelial progenitor cells, EPCs) as it requires signaling by CXCL12, a key chemokine for EPC attraction. As we continue to interrogate how inflammatory neovascularization, autonomously nucleated by IDVCs, unfolds, we anticipate these ongoing investigations will continue to yield even deeper insights into the regulatory crosstalk between these complex biological processes involved in cancer and other diseases. Citation Format: Shih-Chun Shen, James B. DuHadaway, Erika Sutanto-Ward, George C. Prendergast, Alexander J. Muller. Understanding how IDVCs (IDO1-dependent vascularizing cells) respond to and shape the inflammatory milieu to promote neovascularization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5213.