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Dissertation
Exploiting and exploring the role of IDO1-dependent vascularizing cells in supporting inflammatory neovascularization
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2025
DOI:
https://doi.org/10.17918/00010913
Abstract
Tumor-promoting inflammation, as a fundamental modality for shaping the TME, enables cancer cells to acquire hallmark capabilities, including angiogenesis. In response to IFN[gamma], the tryptophan catabolic enzyme IDO1, induced in IDO1-dependent vascularizing cells (IDVCs) as an integral determinant in the inflammatory environment, stimulates the inflammatory cytokine IL6 to counteract the anti-neovascular activity of IFN[gamma] to promote neovascularization in the oncological setting. Therapeutically, in the 4T1 lung metastasis model, inhibiting IDO1 in IDVCs efficiently elevated intra-tumoral hypoxia as a consequence of rapid neovascular reduction, thereby offering an actionable mechanism for enhancing the ability of ischemia-targeted agents to eliminate tumor cells. The resultant signals of immunogenic cell death and PDL1 upregulation further established a positive environment for immune checkpoint blockade responsiveness to improve survival outcomes. The promising therapeutic responses underscore the need to further explore the underlying means by which IDVCs govern the impact of the inflammatory milieu on neovascularization. Mechanistically, to block IFN[gamma]-mediated neovascular regression, IDVCs impeded CXCL10-driven NOS2 activity by downstream activation of IL6 trans-signaling. Notably, IDVCs, in addition to expressing IDO1, concurrently secrete CXCL10 in response to IFN[gamma], suggesting that these cells serve as a nexus linking functionally opposite components. In conjunction with the protective role of IDO1 in vascular retention, IDVCs also intrinsically initiated the vasculogenic process through the recruitment of endothelial progenitor cells (EPCs) to establish the neovasculature. Furthermore, IDVCs may be endowed with an inherent responsibility for maintaining neovascular homeostasis under normal conditions. Collectively, this study highlights a potential IDVC-driven therapeutic intervention stemming from an IDO1 functionality in neovascularization that is independent of adaptive immunity, and reveals a basic framework of how IDVCs orchestrate different compartments in the inflammatory milieu to promote vascular formation. Continued investigations will provide deeper insights into the regulatory crosstalk controlled by IDVCs within malignant settings to inform the mechanistically directed translation towards future therapeutic strategies.
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Details
- Title
- Exploiting and exploring the role of IDO1-dependent vascularizing cells in supporting inflammatory neovascularization
- Creators
- Shih-Chun Shen
- Contributors
- Alexander J. Muller (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022047921004721