FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas

J Natl Cancer Inst. 2015 May 13;107(8):djv137. doi: 10.1093/jnci/djv137. Print 2015 Aug.

Abstract

Background: Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms.

Methods: The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and FcɣRIIB-/- mice (n = 3-18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided.

Results: In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival (P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody (P = .01). The anti-FGL2 antibody treatment reduced CD39(+) Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in FcɣRIIB-/- mice.

Conclusions: FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / blood
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Fibrinogen / genetics
  • Fibrinogen / immunology*
  • Fibrinogen / metabolism
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / blood
  • Glioblastoma / drug therapy
  • Glioblastoma / immunology*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Immunologic Factors / immunology
  • Immunosuppression*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • RNA, Messenger / metabolism
  • Survival Analysis
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Biomarkers, Tumor
  • FGL2 protein, human
  • Immunologic Factors
  • RNA, Messenger
  • Fibrinogen