Innate immune signalling induced by G9a and EZH2 inhibition in ovarian cancer
File(s)
Author(s)
Iyer, Nayana
Type
Thesis or dissertation
Abstract
Ovarian high grade serous carcinoma (HGSC) is the deadliest gynaecological malignancy in the UK and its low survival rates are caused by late presentation and frequent development of resistance to platinum chemotherapy, compounded by a lack of targetable oncogenic drivers and disappointing response rates to immunotherapy. There is increasing realisation that epigenetic mechanisms can contribute to chemoresistance and `cold' tumour immune microenvironments, thereby promoting tumour growth. G9a and EZH2 are histone lysine methyltransferases that are aberrantly expressed in HGSC, and the pharmacological inhibition of both enzymes using a novel dual inhibitor was previously shown in our lab to increase survival of murine HGSC models, modulate the immune microenvironment, and upregulate type I interferon response pathways. This project aimed to understand the individual contributions of inhibiting G9a and EZH2 and the molecular mechanisms by which the immune modulation occurs. Inhibiting G9a, but not EZH2, induced tumour-intrinsic interferon signalling. Systematic inhibition of innate nucleic acid sensing components implicated dsDNA-sensing pathways, but not dsRNA-sensing pathways, in mediating the induction of the interferon responses. This was thought to be a result of impaired dsDNA damage repair following G9a inhibition. Finally, in vivo experiments demonstrated that disrupting tumour intrinsic interferon signalling negated the survival benefit of dual G9a/EZH2 inhibitor treatment, but was insufficient to reverse immune microenvironment changes completely. This project has provided insight into the molecular mechanisms by which G9a inhibition can induce interferon responses in HGSC.
Version
Open Access
Date Issued
2024-07
Online Publication Date
2025-01-03T17:04:18Z
Date Awarded
2024-12
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Costa-Pereira, Ana
McNeish, Iain
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)