Department of Surgery and Cancer, Imperial College London, London, UK.
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
J Immunother Cancer. 2021 Jan;9(1). doi: 10.1136/jitc-2020-001519.
Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC.
ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested , using EOC cell lines and patient-derived tumor cells.
ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). , baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells.
These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect antitumor immunity.
内源性逆转录病毒（ERVs）在多种生物过程中发挥作用，包括胚胎发生和癌症。DNA 甲基转移酶抑制剂（DNMTi）诱导的 ERV 表达通过病毒感应机制触发卵巢癌细胞中的干扰素反应。ERV 在癌细胞中的基础表达也会发生，尽管这一过程在卵巢上皮性癌（EOC）中了解甚少且尚未得到探索。在这里，评估了 EOC 中基础 ERV 表达的预后和免疫调节后果。
使用来自癌症基因组图谱（TCGA）和独立队列（Hammersmith 医院，HH）的 EOC 转录组数据以及未经处理或 DNMTi 处理的 EOC 细胞系评估 ERV 表达。最小绝对收缩和选择算子（LASSO）逻辑回归定义了预测患者预后的 ERV 表达评分。对 HH 队列进行免疫组织化学（IHC）检测。使用 EOC 细胞系和患者来源的肿瘤细胞测试了 DNMTi 治疗与γδ T 细胞的联合治疗。
发现 ERV 表达可定义具有临床意义的 EOC 患者亚群。在 TCGA 中成功生成了 ERV 预后评分，并在独立队列中进行了验证。在来自该队列的 EOC 患者中，高 ERV 评分与更好的生存相关（对数秩检验 p=0.0009），并且与 CD8+PD1+T 细胞浸润相关（r=0.46，p=0.0001）。在 TCGA 数据集，与野生型相比，BRCA1/2 突变肿瘤中发现更高的 ERV 评分（p=0.015），而 CCNE1 扩增肿瘤中发现较低的 ERV 评分（p=0.019）。此外，基础 ERV 表达决定了对 DNMTi 的 ERV 诱导水平。DNMTi 对 ERV 表达阈值的操纵导致细胞毒性免疫细胞对 EOC 细胞的杀伤能力提高。
这些发现揭示了基础 ERV 表达有可能稳健地为 EOC 患者预后提供信息，影响肿瘤免疫浸润并影响抗肿瘤免疫。
