FGL2-wired macrophages secrete CXCL7 to regulate the stem-like functionality of glioma cells. (28th May 2021)

• Record Type: Journal Article
• Authors: Yan, Jun; Zhao, Qingnan; Wang, Jian; Tian, Xiangjun; Wang, Jing; Xia, Xueqing; Ott, Martina; Rao, Ganesh; Heimberger, Amy B.; Li, Shulin
• Is Part Of: Cancer letters. Volume 506(2021)
• Page Start: 83
• Page End: 94
• Publication Date: 2021-05-28
• Subjects: FGL2 -- Macrophages -- Gliomagenesis -- CXCL7 -- CD16; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.02.021
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Glioma stem cells (GSCs) are thought to underlie glioma initiation, evolution, resistance to therapies, and relapse. They are defined by their capacity to initiate glioma in immunocompromised mice which precludes analysis of their interaction with immune cells. Macrophages dominate the immune cell composition in glioma. We hypothesized that stemness and immune evasion induced by macrophages are closed intertwined in glioma. By using mass cytometry and RNA sequencing, we reveal that in immunocompetent mice, FGL2 promotes the stem-like phenotypes of glioma cells in an expression level–dependent manner. Mechanistically, FGL2-producing glioma cells recruit macrophages into the tumor microenvironment and induce the macrophages to secrete CXCL7 via the CD16/SyK/PI3K/HIF1α pathways. CXCL7, in turn, enhances the stem-like functionality of glioma cells, resulting in an increase in tumor incidence and progression that can be blocked with a neutralizing anti-CXCL7 antibody. Clinically, the FGL2-CXCL7 paracrine loop positively correlated with a higher macrophage signature and poorer prognosis in glioma patients. Thus, glioma cells' stem-like functionality is regulated by FGL2 in the presence of macrophages, and the FGL2-CXCL7 paracrine signaling axis is critical for regulating this function. Graphical abstract: Image 1 Highlights: FGL2 promotes tumorigenesis of GL261 cells in an expression level-dependent manner in immunocompetent mice. FGL2 induces CXCL7 expression via CD16/SyK/PI3K/HIF1α pathways in glioma -associated macrophages. CXCL7 promotes sphere formation and tumorigenesis of glioma cells.