MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer
Abstract 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. Howeve...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
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| Series: | Journal of Ovarian Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13048-023-01207-0 |
| _version_ | 1827709039405957120 |
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| author | Yuliang Wu Qi Liu Yan Xie Jihui Zhu Sai Zhang Yao Ge Jing Guo Ning Luo Wei Huang Runping Xu Shupeng Liu Zhongping Cheng |
| author_facet | Yuliang Wu Qi Liu Yan Xie Jihui Zhu Sai Zhang Yao Ge Jing Guo Ning Luo Wei Huang Runping Xu Shupeng Liu Zhongping Cheng |
| author_sort | Yuliang Wu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-10T17:15:24Z |
| format | Article |
| id | doaj.art-8ea840ba02b241169e086f2ccd11ffa2 |
| institution | Directory Open Access Journal |
| issn | 1757-2215 |
| language | English |
| last_indexed | 2024-03-10T17:15:24Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj.art-8ea840ba02b241169e086f2ccd11ffa22023-11-20T10:32:35ZengBMCJournal of Ovarian Research1757-22152023-08-0116111310.1186/s13048-023-01207-0MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancerYuliang Wu0Qi Liu1Yan Xie2Jihui Zhu3Sai Zhang4Yao Ge5Jing Guo6Ning Luo7Wei Huang8Runping Xu9Shupeng Liu10Zhongping Cheng11Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityDepartment of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji UniversityAbstract 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.https://doi.org/10.1186/s13048-023-01207-0MUC16NeutrophilsOvarian cancerTumor immune microenvironmentSiglec-9 |
| spellingShingle | Yuliang Wu Qi Liu Yan Xie Jihui Zhu Sai Zhang Yao Ge Jing Guo Ning Luo Wei Huang Runping Xu Shupeng Liu Zhongping Cheng MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer Journal of Ovarian Research MUC16 Neutrophils Ovarian cancer Tumor immune microenvironment Siglec-9 |
| title | MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| title_full | MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| title_fullStr | MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| title_full_unstemmed | MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| title_short | MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| title_sort | muc16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
| topic | MUC16 Neutrophils Ovarian cancer Tumor immune microenvironment Siglec-9 |
| url | https://doi.org/10.1186/s13048-023-01207-0 |
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