Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX.
Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Natl Cancer Inst. 2019 Mar 1;111(3):292-300. doi: 10.1093/jnci/djy107.
Virtually all low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), including glioblastoma, the most common malignant primary brain tumor in adults. A key regulator of immunosuppression, fibrinogen-like protein 2 (FGL2), may play an important role in the malignant transformation of LGG to HGG. We sought to determine the mechanism of FGL2 on tumor progression and to show that inhibiting FGL2 expression had a therapeutic effect.
We analyzed human gliomas that had progressed from low- to high-grade for FGL2 expression. We modeled FGL2 overexpression in an immunocompetent genetically engineered mouse model to determine its effect on tumor progression. Tumors and their associated microenvironments were analyzed for their immune cell infiltration. Mice were treated with an FGL2 antibody to determine a therapeutic effect. Statistical tests were two-sided.
We identified increased expression of FGL2 in surgically resected tumors that progressed from low to high grade (n = 10). The Cancer Genome Atlas data showed that LGG cases with overexpression of FGL2 (n = 195) had statistically significantly shorter survival (median = 62.9 months) compared with cases with low expression (n = 325, median = 94.4 months, P < .001). In a murine glioma model, HGGs induced with FGL2 exhibited a mesenchymal phenotype and increased CD4+ forkhead box P3 (FoxP3)+ Treg cells, implicating immunosuppression as a mechanism for tumor progression. Macrophages in these tumors were skewed toward the immunosuppressive M2 phenotype. Depletion of Treg cells with anti-FGL2 statistically significantly prolonged survival in mice compared with controls (n = 11 per group, median survival = 90 days vs 62 days, P = .004), shifted the phenotype from mesenchymal HGG to proneural LGG, and decreased M2 macrophage skewing.
FGL2 facilitates glioma progression from low to high grade. Suppressing FGL2 expression holds therapeutic promise for halting malignant transformation in glioma.
几乎所有的低级别胶质瘤（LGG）都会进展为高级别胶质瘤（HGG），包括胶质母细胞瘤，这是成人中最常见的原发性恶性脑肿瘤。纤维蛋白原样蛋白 2（FGL2）是免疫抑制的关键调节剂，它可能在 LGG 向 HGG 的恶性转化中发挥重要作用。我们试图确定 FGL2 对肿瘤进展的机制，并表明抑制 FGL2 表达具有治疗效果。
我们分析了从低级别到高级别进展的人类胶质瘤，以确定 FGL2 的表达情况。我们在免疫活性的基因工程小鼠模型中构建了 FGL2 过表达模型，以确定其对肿瘤进展的影响。分析了肿瘤及其相关微环境中的免疫细胞浸润情况。用 FGL2 抗体治疗小鼠，以确定治疗效果。统计检验为双侧检验。
我们在手术切除的从低级别进展到高级别的肿瘤中发现了 FGL2 的表达增加（n = 10）。癌症基因组图谱（The Cancer Genome Atlas，TCGA）的数据显示，FGL2 过表达的 LGG 病例（n = 195）的中位生存期（62.9 个月）明显短于低表达病例（n = 325，中位生存期为 94.4 个月，P <.001）。在小鼠胶质瘤模型中，FGL2 诱导的 HGG 表现出间充质表型，并增加了 CD4+叉头框 P3（FoxP3）+Treg 细胞，提示免疫抑制是肿瘤进展的一种机制。这些肿瘤中的巨噬细胞向免疫抑制的 M2 表型倾斜。用抗 FGL2 治疗 Treg 细胞耗竭在小鼠中的中位生存期明显长于对照组（每组 11 只，中位生存期分别为 90 天和 62 天，P =.004），肿瘤表型从间充质 HGG 转变为神经前体细胞 LGG，并减少了 M2 巨噬细胞的倾斜。
FGL2 促进了从低级别到高级别的胶质瘤进展。抑制 FGL2 表达有望阻止胶质瘤的恶性转化。
