IMPS-22FGL2 AS A MULTI-MODALITY REGULATOR OF TUMOR-MEDIATED IMMUNE SUPPRESSION

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Tumor remission following standard care for GBM is typically brief and almost invariably followed by tumor recurrence and progression, with a median survival of only 14.6 months. Thus, durable GBM therapy is urgently needed. Immunotherapy has shown promise in obtaining durable responses in melanoma and is currently under investigation in GBM. Here we investigate whether fibrinogen-like protein 2 (FGL2), which shows prothrombinase activity and immune regulatory functions, would serve as a good target for GBM immunotherapy. Our analysis of TCGA data and our laboratory analysis showed that 72.5% of low-grade gliomas maintained two copies of the FGL2 gene, whereas 83.8% of GBMs had gene amplification or copy gain. Furthermore, patients with high levels of FGL2 mRNA in glioma tissues had lower overall survival than those with low levels (p = .009). Protein levels of FGL2 in GBM lysates were higher than in low-grade glioma lysates from patients. Overexpression of FGL2 in glioma cells augmented tumor growth and increased glioma immunosuppression by increasing both the expression levels of immunosuppressive mediators-programmed cell death protein 1 (PD1) and CD39-and the numbers of immunosuppressive CD4+CD39+Foxp3+ regulatory T cells (CD39+ Tregs), CD11b+Gr1+ cells (MDSCs), and M2 macrophages. FGL2 increased M2 and CD39 levels, and PD1 was ablated in FcɣRIIB-/- mice. Of note, treatment with an oligoclonal antibody against FGL2 resulted in elimination of GBM and in long-term survival in 22% of GBM-bearing mice. Collectively, these findings indicate that FGL2 augments glioma immunosuppression by increasing the expression levels of PD1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39+ Tregs. These results show that FGL2 functions as a key immunosuppressive modulator and has potential as an immunotherapeutic target for treating GBM.