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Zhantuyakova, Almira

University of British Columbia

Low-grade serous ovarian carcinoma (LGSC) is a rare ovarian cancer subtype characterized by frequent recurrence and resistance to conventional therapies, highlighting a critical need for innovative treatment approaches. The stimulator of interferon genes (STING) pathway plays a pivotal role in cellular immunity against DNA viruses, while its dysregulation presents a unique opportunity for targeted therapies involving oncolytic viruses. This dissertation provides an in-depth molecular and immunological characterization of LGSC, identifying actionable vulnerabilities and exploring novel immunotherapeutic strategies. The objectives of this thesis were to (i) characterize the proteomic profile and tumor microenvironment of LGSC, (ii) elucidate the regulation and functional status of STING signaling in LGSC, and (iii) evaluate the therapeutic potential of oncolytic vaccinia viruses (OVVs), particularly when engineered with immunostimulatory transgenes targeting the STING pathway. In Chapter 1, I demonstrated a unique proteomic profile distinguishing LGSC from serous borderline tumors and high-grade serous carcinoma, highlighting fibroblast activation protein alpha as a potential marker of invasion and an immunosuppressive tumor microenvironment enriched in regulatory T cells and M2 macrophages. These findings underscore the role of tumor microenvironment modulation in LGSC pathogenesis. In Chapter 2, I revealed impaired STING signaling in LGSC. I identified stromal interaction molecule 1 (STIM1) as a negative regulator of STING activation, with STIM1 silencing restoring STING- driven inflammatory cytokine production. These results position STIM1-STING interactions as promising immunotherapeutic targets in LGSC. In Chapter 3, I investigated the therapeutic potential of OVVs engineered to express DisA (CopDISA), a bacterial cyclic dinucleotide cyclase, exploiting aberrant STING signaling in LGSC. CopDISA infection resulted in robust oncolysis and local STING activation in patient-derived LGSC tumor explants. Single-cell RNA sequencing further revealed tropism of CopDISA for proliferative epithelial tumor cells, and identified immunological shifts marked by increased T cell populations and myeloid cells primed for inflammatory responses. Overall, this dissertation provides insights into the proteomic and immune landscape of LGSC, reveals critical mechanisms underpinning impaired STING signaling, and demonstrates the preclinical efficacy of OVV therapy. These findings significantly advance our understanding of LGSC biology and offer a promising foundation for innovative therapeutics aimed at improving clinical outcomes for LGSC patients.

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2025-07-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/91486

Women+ and Children’s Health Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/