Dissertations and Theses (Open Access)

Author ORCID Identifier

0000-0002-3845-9373

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Anil K. Sood, MD

Committee Member

Zhiqiang An, PhD

Committee Member

Laura Bover, PhD

Committee Member

E. Scott Kopetz, MD, PhD

Committee Member

Kwong K. Wong, PhD

Abstract

Recurrent ovarian cancer is a challenging clinical problem due to the inevitable development of platinum resistance, which necessitates the development of alternative treatments. Despite the impact of immune checkpoint inhibitors on the treatment of various types of cancer, the activity of these agents in ovarian cancer has been dismal. This is largely due to the lack of intratumoral T cell infiltration and the presence of a highly immune suppressive tumor microenvironment. An emerging body of evidence implicates the disorganized vasculature resulting from pathological angiogenesis as playing a key role in immune exclusion. Although treatment with the anti-VEGF-A antibody bevacizumab can prolong progression-free survival, ultimate resistance to this agent invariably develops and overall survival is not improved, highlighting the insufficiency of VEGF-A blockade alone in mitigating pathological blood vessels. We had previously identified epidermal growth factor-like domain 6 (EGFL6) as an additional mediator of pathological angiogenesis in ovarian cancer. EGFL6 is highly expressed in tumor-associated endothelial cells and stromal cells and correlates with immune suppressive conditions, including the abundant presence of M2-like macrophages. EGFL6 promotes the activation of endothelial cells, stromal remodeling and diminishes sensitivity of tumor cells to T cell-mediated killing, consistent with a direct role in the promotion of pathological angiogenesis and immune evasion. Based on these findings, we hypothesized that co-depletion of EGFL6 and VEGF-A would more effectively eradicate the pathological vasculature, diminish tumor growth, and facilitate the entry of immune cells into the tumor. To address this hypothesis, we employed a bispecific antibody targeting both VEGF-A and EGFL6. Co-depletion of VEGF-A and EGFL6 was found to inhibit angiogenic sprouting more effectively than either agent alone in vitro. In vivo, the dual blockade resulted in significantly improved antitumor efficacy and the reprograming of the tumor microenvironment, including decreased immune suppressive cells and increased T cell infiltration. Our data support pathological angiogenesis as contributing to immune exclusion in ovarian cancer. By broadening the scope of targeting to include EGFL6 in addition to VEGF-A, it may be possible to more thoroughly target the angiogenic program to facilitate the creation of an immune-permissive environment. This strategy may provide an alternative approach to improving the efficacy of immune checkpoint inhibitors in this setting.

Keywords

Ovarian cancer, angiogenesis, immune suppression, EGFL6, VEGF-A, anti-angiogenic therapy, antibody therapy, bispecific antibodies

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Available for download on Wednesday, July 07, 2027

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