Cyclin G2 in macrophages triggers CTL-mediated antitumor immunity and antiangiogenesis via interferon-gamma.

Abstract

BACKGROUND:

IFN-γ is a key mediator of tumor immunity that can induce macrophage polarization to suppress tumor growth. Cyclin G2 functions as a tumor suppressor in various cancer cells; however, its role in macrophages remains unclear. This study aimed to investigate the role and underlying mechanisms of cyclin G2 in macrophages in vitro and in vivo.

METHODS:

Mouse tumor models were used to determine the effect of cyclin G2 in macrophages on tumor growth in vivo following IFN-γ treatment. Immunohistochemistry staining, immunofluorescence staining and flow cytometry were used to evaluate the number of cytotoxic T lymphocytes (CTLs) and blood vessels in the mouse tumors. Moreover, the biological roles of cyclin G2 in macrophages with regard to CTL chemotaxis, cytotoxic function, and vascular endothelial cell tube formation were assessed using in vitro functional experiments. Immunoprecipitation (IP), real-time PCR, and enzyme-linked immunosorbent assays (ELISAs) were conducted to investigate the underlying mechanisms by which cyclin G2 regulates CTLs and vascular endothelial cells.

RESULTS:

We found that cyclin G2 expression was upregulated in macrophages after IFN-γ treatment. Upregulated cyclin G2 inhibited lung and colon cancer growth by increasing the secretion of its downstream effector CXCL9, which promoted CTL chemotaxis and suppressed vascular endothelial cell tube formation. Moreover, cyclin G2 increased CXCL9 mRNA levels by promoting STAT1 nuclear translocation. In addition, cyclin G2 promoted the activation of the STAT1 signaling pathway, which was dependent on PP2Ac.

CONCLUSIONS:

Cyclin G2 is upregulated by IFN-γ in macrophages, promotes the secretion of CXCL9 to increase CTL chemotaxis and inhibit angiogenesis to suppress tumor growth. Our findings suggest that targeting cyclin G2 could benefit future immunotherapy.

• Authors: Lu Liu, Jinlan Gao, Xuesha Xing, Meixi Jiang, Qi Liu, Shusen Wang, Yang Luo
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 41 Issue 1 Pg. 358 (Dec 24 2022) ISSN: 1756-9966 [Electronic] England
• PMID: 36566226 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Cyclin G2
• Interferon-gamma

Topics

• Animals
• Mice
• Cell Line, Tumor
• Cyclin G2 (metabolism)
• Endothelial Cells (metabolism)
• Immunotherapy
• Interferon-gamma (metabolism)
• Macrophages (metabolism)
• T-Lymphocytes, Cytotoxic (metabolism)
• Neoplasms (blood supply, immunology)
• Neovascularization, Pathologic (metabolism)