Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University, 301 Yanchang Road, Shanghai, 200072, China.
Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China.
J Ovarian Res. 2023 Aug 30;16(1):181. doi: 10.1186/s13048-023-01207-0.
BACKGROUND: MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored. METHODS: The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro. RESULTS: The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b, CD66b, and ICAM-1 neutrophils were significantly increased, while the proportion of CXCR4 neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro. CONCLUSION: MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.
背景：MUC16（CA125）是一种常用于卵巢癌筛查的肿瘤标志物，据报道，它通过作用于自然杀伤细胞（NK 细胞）、B 细胞和单核细胞表面的唾液酸结合免疫球蛋白样凝集素-9（Siglec-9），成为一种免疫抑制因子。然而，MUC16 在肿瘤微环境中的中性粒细胞中的作用仍有待进一步探索。
方法：基于临床样本，构建了患者外周血细胞比例和计数、血清炎症相关因子与血清 MUC16（CA125）水平之间的相关性。从 TCGA 获得 RNAseq 数据和卵巢癌组织测序，然后进行 TIMER 免疫细胞浸润和相关性分析。构建卵巢癌类器官，通过 qPCR 和流式细胞术对免疫表型进行鉴定，刺激中性粒细胞。通过 RNA 测序分析和体外抑制 NK 细胞毒性验证 MUC16 蛋白对中性粒细胞的作用。
结果：血清 MUC16 水平与外周血中性粒细胞比例和计数、中性粒细胞与淋巴细胞比值（NLR）以及炎症因子 IL-6、IL-8、IL-10 和 IL-2R 呈正相关。MUC16 的受体 Siglec-9 在中性粒细胞上表达，并与卵巢癌中的中性粒细胞浸润呈正相关。卵巢癌类器官刺激和 MUC16 刺激后，CD11b、CD66b 和 ICAM-1 中性粒细胞的比例明显增加，而 CXCR4 中性粒细胞的比例略有下降，同时炎症因子 MMP9、IL-8、OSM、IL-1β、TNF-α、CXCL3 和 ROS 水平升高。RNA 测序分析显示，MUC16 刺激的中性粒细胞中炎症反应、TNFA 信号通路和 IL6 相关通路上调，同时免疫抑制相关因子 HHLA2、IL-6、TNFRSF9、ADORA2A、CD274（PD-L1）和 IDO1 表达上调。体外实验中，MUC16 刺激的中性粒细胞上清液处理后 NK 细胞毒性降低。
结论：MUC16 通过 Siglec-9 作用于中性粒细胞，导致卵巢癌中产生炎症和免疫抑制表型。
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