Chronic inflammation influences the tumor immune microenvironment (TIME) in high-grade serous ovarian cancer (HGSOC). Specifically, cyclooxygenase-2 (COX-2) overexpression promotes cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression. Notably, elevated COX-2 levels in the TIME have been associated with reduced response to anti-CTLA-4 immunotherapy. However, the precise impact of COX-2, encoded byPTGS2, on the immune profile remains unknown. To address this, we performed an integrated bioinformatics analysis using data from the HGSOC cohorts (TCGA-OV,n= 368; Australian cohort AOCS,n= 80; GSE26193,n= 62; and GSE30161,n= 45). Employing Gene Set Variation Analysis (GSVA), MIXTURE and Ecotyper cell deconvolution algorithms, we concluded that COX-2 was linked to immune cell ecosystems associated with shorter survival, cell dysfunction and lower NK cell effector cytotoxicity capacity. Next, we validated these results by characterizing circulating NK cells from HGSOC patients through flow cytometry and cytotoxic assays while undergoing COX-2 and CTLA-4 blockade. The blockade of COX-2 improved the cytotoxic capacity of NK cells against HGSOC cell lines. Our findings underscore the relevance of COX-2 in shaping the TIME and suggest its potential as a prognostic indicator and therapeutic target. Increased COX-2 expression may hamper the effectivity of immunotherapies that require NK cell effector function. These results provide a foundation for experimental validation and clinical trials investigating combined therapies targeting COX-2 and CTLA-4 in HGSOC.
慢性炎症影响高级别浆液性卵巢癌（HGSOC）的肿瘤免疫微环境（TIME）。具体而言，环氧合酶-2（COX-2）的过度表达促进细胞毒性T淋巴细胞相关蛋白-4（CTLA-4）的表达。值得注意的是，TIME中COX-2水平升高与抗CTLA-4免疫疗法的反应降低相关。然而，由PTGS2编码的COX-2对免疫特征的确切影响仍不清楚。为解决这一问题，我们利用HGSOC队列数据（TCGA-OV，n=368；澳大利亚队列AOCS，n=80；GSE26193，n=62；以及GSE30161，n=45）进行了综合生物信息学分析。通过采用基因集变异分析（GSVA）、MIXTURE和Ecotyper细胞反卷积算法，我们得出结论：COX-2与生存期缩短、细胞功能障碍及NK细胞效应细胞毒性能力降低相关的免疫细胞生态系统有关。接下来，我们通过流式细胞术和细胞毒性实验对接受COX-2和CTLA-4阻断治疗的HGSOC患者的循环NK细胞进行表征，验证了这些结果。阻断COX-2提高了NK细胞对HGSOC细胞系的细胞毒性能力。我们的研究结果强调了COX-2在塑造TIME中的重要性，并提示其作为预后指标和治疗靶点的潜力。COX-2表达增加可能阻碍依赖NK细胞效应功能的免疫疗法的有效性。这些结果为实验验证和临床试验研究HGSOC中靶向COX-2和CTLA-4的联合疗法奠定了基础。
肿瘤(癌症)患者之家