The CXCLs-CXCR2 axis modulates the cross-communication between tumor-associated neutrophils and tumor cells in cervical cancer

ABSTRACT

Objective

This study aimed to check the expression profile of the C-X-C motif chemokine ligands (CXCLs)-C-X-C motif chemokine receptor 2 (CXCR2) axis in cervical cancer and to explore the cross-talk between cervical cancer cells and neutrophils via CXCLs-CXCR2 axis.

Methods

Available RNA-sequencing data based on bulk tissues and single-cell/nucleus RNA-sequencing data were used for bioinformatic analysis. Cervical cancer cell lines Hela and SiHa cells were utilized for in vitro and in vivo studies.

Results

Except for neutrophils, CXCR2 mRNA expression is limited in other types of cells in the cervical tumor microenvironment. CXCLs bind to CXCR2 and are mainly expressed by tumor cells. CXCL1, 2, 3, 5, 6, and 8, which are consistently associated with neutrophil infiltration, are also linked to poor prognosis. SB225002 (a CXCR2 inhibitor) treatment significantly impairs SiHa cell-induced neutrophil migration. CXCL1, CXCL2, CXCL5, or CXCL8 neutralized conditioned medium from SiHa cells have weaker recruiting effects. The conditioned medium of neutrophils from healthy donors can slow cancer cell proliferation. Conditioned medium of tumor-associated neutrophils (TANs) can drastically enhance cervical cancer cell growth in vitro and in vivo.

Conclusions

The CXCLs-CXCR2 axis is critical in neutrophil recruitment and tumor cell proliferation in the cervical cancer microenvironment.

KEYWORDS:

• Cervical cancer
• neutrophil
• CXCLs
• CXCR2
• cell growth

Article highlights

• CXCR2 is extensively expressed in neutrophils but with limited expression in cervical cancer cells.

• CXCL1-3, CXCL5-6, and CXCL8 are expressed in malignant tumor cells in cervical cancer.

• CXCL1-3, 5-6, and 8 expression are associated with poor prognosis and neutrophil infiltration in cervical cancer.

• CXCL1-3, 5-6, and 8 stimulate neutrophil migration via CXCR2.

• Tumor-associated neutrophils (TANs) promote cervical cancer cell proliferation.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics statement

Ethical review and approval were obtained from the ethics committee of Fujian Cancer Hospital (Approval no. SQ2022–230 and IACUC-FPH-SL-20230911[0096]).

Data availability statement

Data is contained within the article.

Additional information

Funding

This study was funded by the Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province, China [Grant No. 2022ZQNZD008].