MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer

Journal of Ovarian Research

Research

Sai Zhang¹  Jihui Zhu¹  Yao Ge²  Qi Liu²  Zhongping Cheng²  Shupeng Liu²  Yan Xie²  Runping Xu²  Wei Huang²  Jing Guo²  Yuliang Wu²  Ning Luo² 

[1] Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji University, 301 Yanchang Road, 200072, Shanghai, China;Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji University, 301 Yanchang Road, 200072, Shanghai, China;Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, 200092, Shanghai, China;

关键词: MUC16;    Neutrophils;    Ovarian cancer;    Tumor immune microenvironment;    Siglec-9;   

DOI  :  10.1186/s13048-023-01207-0

 received in 2022-11-06, accepted in 2023-06-16,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMUC16 (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.MethodsThe 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.ResultsThe 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.ConclusionMUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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