Decreased CXCR2 expression on circulating monocytes of colorectal cancer impairs recruitment and induces Re-education of tumor-associated macrophages

Though circulating monocytes are the main source of tumour-associated macrophages (TAMs), the regulatory mechanisms of their recruitment to tumours and further differentiation remain unclear. In the present study, we observed a significant decrease in CXCR2 expression in classical circulating monocy...

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Bibliographic Details
Published in:Cancer letters 2022-03, Vol.529, p.112-125
Main Authors: Wang, Huayang, Shao, Qianqian, Wang, Jiaoyang, Zhao, Lei, Wang, Liyang, Cheng, Zhiqiang, Yue, Congbo, Chen, Wendan, Wang, Hongchun, Zhang, Yi
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Antibodies
Biomarkers
Cancer
Cell differentiation
Cell Line, Tumor
Chemotaxis
Chemotaxis, Leukocyte - genetics
Chemotaxis, Leukocyte - immunology
Cloning
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - etiology
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
CXCR2
CXCR2 protein
Cytokines
Female
Flow cytometry
Gene Expression
Gene Knockdown Techniques
Humans
Immunophenotyping
Inflammation
Interferon-γ
Lipopolysaccharides
Macrophages
Male
Metastases
Microenvironments
Middle Aged
Monocytes
Monocytes - immunology
Monocytes - metabolism
Neoplasm Staging
Phenotypes
Receptors, Interleukin-8B - genetics
Receptors, Interleukin-8B - metabolism
Tumor microenvironment
Tumor Microenvironment - genetics
Tumor Microenvironment - immunology
Tumor-Associated Macrophages - immunology
Tumor-Associated Macrophages - metabolism
Tumors
Tumour-associated macrophages
γ-Interferon
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Summary:Though circulating monocytes are the main source of tumour-associated macrophages (TAMs), the regulatory mechanisms of their recruitment to tumours and further differentiation remain unclear. In the present study, we observed a significant decrease in CXCR2 expression in classical circulating monocytes of patients with colorectal cancer (CRC), particularly those in the late TNM stage. The percentage of CXCR2+ monocytes was negatively associated with systemic inflammatory markers and positively associated with intratumoural immunocyte infiltration. The pro-inflammatory cytokine IFN-γ, which was overexpressed in patients with CRC, down-regulated CXCR2 expression of monocytes/TAMs by promoting GRK-2 expression. In vitro, inhibition of CXCR2 signalling in monocytes led to impaired chemotaxis to the tumour cell line supernatant and lower responsiveness to lipopolysaccharide (LPS) stimulation. Finally, monocytes from patients with CRC with decreased CXCR2 expression showed distinct phenotypes and functions after differentiating into CRC cell line-educated TAMs, including expression of co-stimulatory factors and secretion profile, than those from healthy controls. GRK-2 inhibitor altered the functional characteristics of TAMs. In summary, our findings suggest that CXCR2 expression on circulating monocytes reflects CRC stages and is an important factor determining TAM composition in the tumour microenvironment. •CXCR2+ classical monocytes are decreased in CRC patients.•CXCR2+ monocytes percentage changes with TNM stages.•IFN-γ decreases CXCR2 on monocytes by up-regulating GRK-2.•CXCR2 regulates chemotaxis of monocytes toward CRC.•CXCR2 induces functional re-programming of TAMs.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2022.01.004