The role of innate immune responses in oncolytic adenovirus therapy in ovarian cancer

Leung, Elaine Yee Ling (2018) The role of innate immune responses in oncolytic adenovirus therapy in ovarian cancer. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Epithelial ovarian cancer is the deadliest gynaecological cancer: most women die within five years of their diagnoses. Moreover, survival of women with ovarian cancer (OC) has not significantly improved in the past decade. Oncolytic viruses (OVs), a new class of anti-cancer agent, infect and replicate selectively within malignant cells, whilst sparing normal cells. OVs also induce profound immune responses, for example disruption of chemokine and cytokine networks, with potential influence on therapeutic effectiveness. On the other hand, Natural Killer cells (NK cells), a key immune population that surveillance against cancers and viruses, may hinder the spread of OVs or promote anti-tumoural effects of OVs. This work investigated the role of innate immune responses, in particular NK cells and interleukin (IL)-17F, on the efficacy of oncolytic adenovirus in OC.

I demonstrated that NK cells were activated by adenovirus-infected OC cells. Activated NK cells then augmented oncolytic adenovirus in eliminating OC via contact-dependent interactions between activating NK receptor DNAM-1 and adenovirus-infected malignant cells.

In addition, consistent changes in chemokines and cytokines were observed after wild-type and oncolytic adenovirus infection. In particular, IL-17F, but not IL-17A, was significantly upregulated in different established and primary OC lines after adenovirus infections. Moreover, a range of inflammatory chemokines, including CCL2, CXCL1, CXCL2 and CXCL5, were down-regulated after oncolytic adenovirus infection.

This work also revealed the logistical and technical challenges of the use of primary patient materials. I identified that our primary culture method for expanding OC cells was suboptimal. I subsequently evaluated a simple immunohistochemical method to screen for successful primary expansion of malignant cells from OC ascites. I showed that PAX8, but not CK7, was a specific marker of successful ex vivo expansion of HGSOC.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: immunotherapy, ovarian cancer, neoplasm, oncolytic viruses, biomarker, tissue culture, chemokines, IL-17, natural killer cells.
Subjects: R Medicine > RG Gynecology and obstetrics
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Translational Research Centre
Funder's Name: Wellcome Trust (WELLCOTR)
Supervisor's Name: McNeish, Professor Iain A.
Date of Award: 2018
Embargo Date: 31 December 2019
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:2018-30608
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Jun 2018 08:14
Last Modified: 25 Jul 2018 09:55
URI: http://theses.gla.ac.uk/id/eprint/30608

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