title: FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas.
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.
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Konrad
authors.initials: K
authors.lastname: Gabrusiewicz
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Denada
authors.initials: D
authors.lastname: Dibra
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX. sli4@mdanderson.org aheimber@mdanderson.org.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
authors.affiliation: Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX. sli4@mdanderson.org aheimber@mdanderson.org.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; C095202:FGL2 protein, human; D007155:Immunologic Factors; D012333:RNA, Messenger; D005340:Fibrinogen