Decreased CXCR2 expression on circulating monocytes of colorectal cancer impairs recruitment and induces Re-education of tumor-associated macrophages. (31st March 2022)

• Record Type: Journal Article
• Authors: Wang, Huayang; Shao, Qianqian; Wang, Jiaoyang; Zhao, Lei; Wang, Liyang; Cheng, Zhiqiang; Yue, Congbo; Chen, Wendan; Wang, Hongchun; Zhang, Yi
• Is Part Of: Cancer letters. Volume 529(2022)
• Page Start: 112
• Page End: 125
• Publication Date: 2022-03-31
• Subjects: Colorectal cancer -- Monocytes -- CXCR2 -- Interferon-γ -- Tumour-associated macrophages; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.01.004
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: 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.