The Duality of Fgl2 - Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications

Hu, Jiemiao; Yan, Jun; Rao, Ganesh; Latha, Khatri; Overwijk, Willem W.; Heimberger, Amy B.; Li, Shulin

doi:10.3109/08830185.2014.956360

Cited by 43 publications

(63 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Expression of key genes known to be involved in clotting and glioma-associated thrombosis [21, 22, 33, 45, 47, 62] (Supplemental Table 5) was assessed via Illumina HiSeq 2000 RNA Sequencing platform in grade II-IV TCGA gliomas. Each row represents a single tumor, columns indicate either IDH1/2 status (aqua = IDH2 mutant, red = IDH1 mutant, black = IDH1/2 wild-type); WHO grade (peach = II, green = III, purple = IV); or gene expression as a ratio of the individual tumor mRNA relative to the mean of all IDH1/2 wild-type tumors for that gene (blue = downregulated, yellow = upregulated, white = no change).…”

Section: Figmentioning

confidence: 99%

Mutant IDH1 and thrombosis in gliomas

Unruh¹,

et al. 2016

View full text Add to dashboard Cite

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for Tissue Factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26–30% of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0%). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85–90% in wild-type versus 2–6% in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

show abstract

Section: Figmentioning

confidence: 99%

Mutant IDH1 and thrombosis in gliomas

Unruh¹,

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Fibrinogen‐like protein 2 (FGL2), a member of the fibrinogen family, is expressed either as a pro‐coagulative membrane protein or as an immunosuppressive secreted protein . FGL2 over‐expression resulted in deterioration of heart function in rats with acute EAM, increased the inflammatory cell infiltrations, and increased the level of brain natriuretic peptide (BNP), tumour necrosis factor‐ α , interleukin‐6 (IL‐6) and IL‐17 Increased expression of PD‐1/PD‐L1 in ischaemia re‐perfused and cryoinjured hearts was associated with a marked increase in IL‐17 .…”

Section: Introductionmentioning

confidence: 99%

“…Abbreviations: BNP, brain natriuretic peptide; EAM, experimental autoimmune myocarditis; FGL2, fibrinogen-like protein-2; Foxp3, transcription factor forkhead box P3; IFN-c, interferon-c; IL-6, interleukin-6; PD-1, programmed death-1; RORct retinoic acid-related orphan receptor ct; Th17, T helper type 17; Treg, regulatory T; VMC, viral myocarditis Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, is expressed either as a pro-coagulative membrane protein or as an immunosuppressive secreted protein. 8 FGL2 over-expression resulted in deterioration of heart function in rats with acute EAM, increased the inflammatory cell infiltrations, and increased the level of brain natriuretic peptide (BNP), tumour necrosis factora, interleukin-6 (IL-6) and IL-17 9 Increased expression of PD-1/PD-L1 in ischaemia re-perfused and cryoinjured hearts was associated with a marked increase in IL-17. 10 In our current study we explored the involvement of the PD-1/PD-L1 pathway in immunotolerance as a potential mechanism for the pathogenesis of EAM mediated by FGL2.…”

Section: Introductionmentioning

confidence: 99%

Fibrinogen‐like protein‐2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death‐1 and inflammatory cytokines

Zhang

Potla

et al. 2017

Immunology

View full text Add to dashboard Cite

Programmed death-1 (PD-1) plays an important role in protecting against inflammation and myocyte damage in T-cell-mediated myocarditis. To understand whether fibrinogen-like protein-2 (FGL2) can affect the role of the PD-1/PD-L1 pathway in experimental autoimmune myocarditis (EAM), we investigated cardiac function in EAM rats over-expressing FGL2. Over-expression of FGL2 significantly decreased PD-1 and deteriorated cardiac function in rats with autoimmune myocarditis. Histopathology revealed increased inflammatory cell infiltrate in EAM-FGL2 rats compared with the control groups (EAM, EAM-GFP and NC). Notably, transcription factor forkhead box P3 (Foxp3) and retinoic acid-related orphan receptor γt (RORγt) protein and mRNA levels were statistically (P < 0·05) increased in EAM rats. We also found that interferon-γ, interleukin-6, interleukin-17 and brain natriuretic peptide levels were profoundly increased in serum of FGL2 over-expressing EAM rats. Hence, FGL2 plays an important role in the pathogenesis of autoimmune myocarditis that also involves the PD-1/PD-L1 pathway. Our findings may provide novel therapeutic targets for the treatment of immune-induced heart injury.

show abstract

“…Fibrinogen-like protein 2 (FGL2) is a member of the brinogen superfamily with prothrombin activity and multiple functions in immune regulation. FGL2 is highly expressed in various tumour tissues and plays a vital role in tumour occurrence and progression [10,11,12]. As an immunoregulatory factor, FGL2 has been shown to play a multimodal role in the innate and acquired immune responses, including enhanced activation of T regulatory cells (Tregs) and maintenance of their immunosuppressive activity, a balanced ratio of Th1 and Th2 cells, and inhibition of antigen-presenting activity [13,14].…”

Section: Introductionmentioning

confidence: 99%

Tumour-Associated Macrophage Polarisation Promotes Progression of Esophageal Carcinoma

Yuan

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: The immune response mediated by tumour-associated macrophages (TAMs) is vital in tumour progression in many cancers. Fibrinogen-like protein 2 (FGL2) is a critical immunosuppressive factor that regulates the tumour microenvironment. However, no study has yet reported on the relationship between FGL2, tumour-infiltrating lymphocyte recruitment, and prognosis in esophageal carcinoma (ESCA). Methods: Differentially expressed genes (DEGs) in various macrophage phenotypes were analysed using the GEO database. We identified the hub genes involved in affecting ESCA clinical prognosis using Kaplan-Meier plotter. Correlations between hub genes and immune infiltrates were analysed using the Tumour Immune Estimation Resource (TIMER) database, while correlation analysis between FGL2 and cytokine expression was assessed using cBioPortal. In vitro cell co-culture experiments were performed to examine the role of FGL2 in promoting tumorigenesis. Finally, we compared the GO terms and KEGG pathways enriched by the DEGs in M1 and M2 macrophages using DAVID.Results: High FGL2 expression was significantly associated with poorer overall survival and relapse-free survival of esophageal cancer patients. FGL2 expression was positively correlated with immune markers and infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells. In addition, FGL2 expression was strongly correlated to IL-10, MMP9, CCL5, TIM-3, IL-13, VCAM1, M-CSF and FGF-7 expression. Conclusions: M2-like TAMs may regulate the tumour microenvironment by secreting FGL2, thereby inducing the occurrence and progression of ESCA. Reversing TAM polarization may be an effective strategy that reveals new targets for immunotherapy in treating ESCA.

show abstract

The Duality of Fgl2 - Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications

Cited by 43 publications

References 90 publications

Mutant IDH1 and thrombosis in gliomas

Mutant IDH1 and thrombosis in gliomas

Fibrinogen‐like protein‐2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death‐1 and inflammatory cytokines

Tumour-Associated Macrophage Polarisation Promotes Progression of Esophageal Carcinoma

Contact Info

Product

Resources

About