Cargando…
MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer
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 r...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466733/ https://www.ncbi.nlm.nih.gov/pubmed/37644468 http://dx.doi.org/10.1186/s13048-023-01207-0 |
_version_ | 1785098953885220864 |
---|---|
author | Wu, Yuliang Liu, Qi Xie, Yan Zhu, Jihui Zhang, Sai Ge, Yao Guo, Jing Luo, Ning Huang, Wei Xu, Runping Liu, Shupeng Cheng, Zhongping |
author_facet | Wu, Yuliang Liu, Qi Xie, Yan Zhu, Jihui Zhang, Sai Ge, Yao Guo, Jing Luo, Ning Huang, Wei Xu, Runping Liu, Shupeng Cheng, Zhongping |
author_sort | Wu, Yuliang |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-023-01207-0. |
format | Online Article Text |
id | pubmed-10466733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-104667332023-08-31 MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer Wu, Yuliang Liu, Qi Xie, Yan Zhu, Jihui Zhang, Sai Ge, Yao Guo, Jing Luo, Ning Huang, Wei Xu, Runping Liu, Shupeng Cheng, Zhongping J Ovarian Res Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-023-01207-0. BioMed Central 2023-08-30 /pmc/articles/PMC10466733/ /pubmed/37644468 http://dx.doi.org/10.1186/s13048-023-01207-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Wu, Yuliang Liu, Qi Xie, Yan Zhu, Jihui Zhang, Sai Ge, Yao Guo, Jing Luo, Ning Huang, Wei Xu, Runping Liu, Shupeng Cheng, Zhongping MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer |
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 | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466733/ https://www.ncbi.nlm.nih.gov/pubmed/37644468 http://dx.doi.org/10.1186/s13048-023-01207-0 |
work_keys_str_mv | AT wuyuliang muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT liuqi muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT xieyan muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT zhujihui muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT zhangsai muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT geyao muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT guojing muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT luoning muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT huangwei muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT xurunping muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT liushupeng muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer AT chengzhongping muc16stimulatesneutrophilstoaninflammatoryandimmunosuppressivephenotypeinovariancancer |