Effect of platinum chemotherapy on tumour infiltrating immune cells in metastatic ovarian cancer: Mechanistic insights and therapeutic applications

Platinum chemotherapeutics remain standard of care for many cancer patients, including high grade serous ovarian cancer. It is becoming clear that chemotherapy can initiate adaptive immune responses to the cancer, however, it remains unclear to what extent innate Natural Killer (NK) cells contribute. Using two syngeneic models (UPK10 and ID8p53^-/-) of metastatic ovarian cancer this thesis found that treatment with carboplatin upregulates NK cell activating receptor ligands, induced a pro-inflammatory phenotype and sensitised tumour cells to NK cell mediated cytotoxicity. *In vivo*, carboplatin therapy was dependent on the presence of NK cells and CD8⁺ T cells and treatment with carboplatin resulted in an enrichment for NK cells and CD8⁺ T cells within the tumour. This effect however was model dependent. Therapeutically, Il-15/IL-15Rα treatment increased the numbers of cytotoxic NK cells at sites of metastasis, which significantly reduced tumour burdens in mice when used in combination with carboplatin. Collectively, these findings demonstrated the importance of NK cells as mediators of standard cancer therapy and represents an attractive and relatively safe therapeutic target for combination therapy.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Boyles, Christabel

Advisor dc:contributor.advisor

• Halim, Timotheus

• Carboplatin
• High-grade serous ovarian cancer
• Natural killer cells

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f2d2d0b2-ed87-4231-bce4-20db99931edc/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.109815

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/370379