부산대학교 도서관

Immunotherapeutic strategies for ovarian cancer (OC) patients have so far failed to show any benefit in clinical trials. Novel combination strategies are being developed to enhance immune function in these patients by overcoming immunosuppressive mechanisms present within the ovarian tumour microenvironment. Epigenetic modifying agents, such as DNA methyltransferase inhibitors (DNMTi), have shown some promise in synergising with immunotherapy in OC in preclinical studies and early clinical trials. Furthermore, a role for DNMTi-induced endogenous retrovirus (ERV) expression in enhancing response to immunotherapy has recently been suggested. Here, DNMTi-driven immunomodulation was investigated using in vitro models of ovarian cancer and immune cell interactions. The effect of DNMTi treatment of OC cell lines on transcription of ERVs was also investigated, together with the prognostic and immunomodulatory consequences of baseline ERV expression in OC cell lines and ovarian tumours. DNMTi treatment of OC cell lines was shown to enhance activation of previously unstimulated immune cells as well as killing of tumour cells by activated effector immune cells. Transcriptomic analysis revealed upregulation of gene and ERV expression in OC cell lines, following DNMTi treatment. Particularly, an enrichment for adaptive and innate immunomodulatory genes was observed in DNMTi-treated cell lines, compared to vehicle-treated controls. Analysis of baseline gene and ERV expression in two OC cell lines revealed transcriptional differences, including distinct levels of ERV expression, which may affect each OC cell line's response to DNMTi and immune cell attack. Interrogation of transcriptomic data from OC samples from TCGA revealed that ERV expression defines subsets of OC patients. Moreover, expression of single ERV repeats was associated with patient prognosis and significantly correlated with expression of immune genes and signatures. Finally, an ERV prognostic model was generated to predict patient prognosis, based on expression of selected ERVs. These findings highlight a role for DNMTi treatment of OC cells in enhancing immune activation via induction of ERVs and immunomodulatory genes as well as the potential for baseline ERV expression in OC to inform patient prognosis and influence local tumour immunogenicity.