Immunomodulatory action of demethylating agent SGI-110 in ovarian cancer

卵巢癌（OC）被认为是一种免疫原性癌症，然而，与卵巢癌相关的大部分免疫反应本质上是炎症和抑制性的。这表明克服这些抑制机制和增强患者免疫功能的策略将带来益处并改善预后。免疫疗法已被证明是最有希望的，当与其他治疗方法相结合，以对抗疾病。该领域的最新证据和我们小组的初步数据表明，用胞苷类似物等表观遗传药物治疗可以改善包括卵巢癌在内的几种癌症的免疫激活。我们假设胞苷类似物治疗的整体去甲基化和DNA损伤效应可以诱导免疫调节基因和内源性逆转录病毒元件（ERVs）的重新表达，从而使卵巢癌细胞转向更具免疫原性的表达谱。我们计划通过新型胞苷类似物SGI-110处理的卵巢癌细胞系的rna测序来鉴定和验证这些免疫调节基因和erv；研究DNA去甲基化和DNA损伤在这类表观遗传药物的免疫调节作用中的作用，并测试使用SGI-110和t细胞治疗卵巢癌的一种新的表观遗传-免疫联合治疗策略。该项目将首次采用基因组学方法研究SGI-110的免疫调节潜能，并为以前未研究的卵巢癌细胞系提供更能代表真实疾病的全基因组转录数据。此外，它将确定潜在的基因靶点和/或生物标志物，并测试一种新的联合疗法，最终可能会发展成临床试验。

Ovarian cancer (OC) is regarded as being an immunogenic cancer, however, the bulk of the immune responses associated with OC are inflammatory and suppressive in nature. This suggests that strategies to overcome these suppressive mechanisms and enhance immune function in patients will confer benefit and improve prognosis. Immunotherapy has been shown to be most promising when combined with other therapeutic approaches to combat the disease. Recent evidence in the field and preliminary data from our group suggest that treatment with epigenetic drugs, such as cytidine analogs, can lead to improved immune activation in several cancers including ovarian. We hypothesise that the global demethylating and DNA damaging effects of treatment with cytidine analogs can induce the re-expression of immunomodulatory genes and endogenous retroviral elements (ERVs), which shifts ovarian cancer cells towards a more immunogenic expression profile. We plan to identify and validate such immunomodulatory genes and ERVs by RNA-sequencing of ovarian cancer cell lines treated with novel cytidine analog SGI-110; to investigate the contribution of DNA demethylation and DNA damage in the proposed immunomodulatory effect of this class of epigenetic drugs and to test a novel combination epigenetic-immunotherapeutic strategy for the treatment of ovarian cancer using SGI-110 and T-cells. This project will, for the first time, use a genomic approach to study the immunomodulatory potential of SGI-110 and provide genome-wide transcriptional data for previously unstudied ovarian cancer cell lines which better represent the real disease. Additionally, it will identify potential gene targets and/or biomarkers and test a novel combination therapy which may, ultimately, be developed into a clinical trial.