| الوصف: |
Despite ample clinical evidence that prognosis of patients with advanced ovarian cancer is critically dependent on the anti-tumour immune response, cancer immunotherapy treatments have failed to achieve a meaningful survival benefit for many patients. A need to potentiate the host’s immune response against ovarian cancer cells is therefore imperative. Ovarian cancer cells manage to evade immune responses by altering the epigenome in a way that it can modulate all steps of the immune cycle. This includes antigen presentation, lymphocyte priming, activation and trafficking, as well as cytotoxic lymphocyte effector functions. DNA methylation and histone deacetylation were the two mechanisms initially identified to play a crucial role in immune evasion, with histone methylation being an important emerging pathway too. In this PhD project, I initially sought to discover novel epigenetic mechanisms involved in the immune process in a Trp53-/- murine model of ovarian cancer by undertaking a medium-throughput screening with a library of novel epigenetic probes. G9a and EZH2 histone lysine methyltransferases emerged as mechanisms implicated in the release of lymphocyte chemotactic chemokines, such as CXCL9, CXCL10 and CXCL11. By using a novel dual inhibitor and with a combination of cellular, transcriptional and chromatin accessibility assays, I observed that simultaneous inhibition of G9a and EZH2 modulated the tumour immune microenvironment. I observed a transcriptional upregulation of immune pathways, coupled with cellular changes that represented a favourable immune profile intratumorally. The cellular changes included modulation of CD8+ lymphocyte phenotype, an increase in the presence of Natural Killer cells and an increase in expression of CXCR3, the receptor for CXCL9-11 chemokines. Moreover, these alterations in the immune microenvironment were accompanied by a modest therapeutic effect. The results of this thesis highlight the importance of inhibiting G9a/EZH2 in Trp53-/- ovarian cancer. |
