原发性脑肿瘤中的免疫细胞浸润与炎症景观

原发性恶性脑肿瘤占所有脑肿瘤的三分之一以上，尽管通过分子研究试图鉴定癌症驱动突变，但由于肿瘤内异质性较高，目前的治疗方案仍面临挑战。此外，免疫抑制和炎症的肿瘤微环境增强了癌症的进展。因此，我们对脑膜瘤和胶质瘤的免疫与炎症特征进行了分析，以阐明免疫浸润在这些癌症类型中的作用。利用158例脑肿瘤样本的组织微阵列，通过免疫组化（IHC）检测CD3、CD4、CD8、CD20、CD138、Granzyme B（GzmB）、5-脂氧酶（5-LOX）、程序性死亡配体1（PD-L1）、O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）和转谷氨酰胺酶2（TG2）的表达。IHC结果通过斯皮尔曼相关矩阵分析。利用GEPIA2公开数据库中的数据，评估了胶质母细胞瘤（GBM）和低级别胶质瘤（LGG）队列中的转录表达、相关性及总生存期（OS）。结果显示，十个标志物中有七个在至少一个队列中表现出显著的差异表达，其中CD3、CD4和5-LOX在GBM与星形细胞瘤之间存在差异。相关性分析揭示，5-LOX与GzmB在脑膜瘤和GBM中均相关，且在脑膜瘤与星形细胞瘤中，5-LOX表达明显且正相关于TG2。通过TCGA-GBM和LGG数据集的相关性分析验证了这些发现。mRNA表达分析显示，GBM中CD3（CD3D、CD3E）和CD138（SDC1）表达显著升高。CD4和5-LOX（ALOX5）在肿瘤样本中比正常组织表达更高。在GBM队列中，GzmB（GZMB）、SDC1和MGMT的基因表达预示着较差的总生存期（OS）。在LGG队列中，CD3（CD3D、CD3E、CD3G）、CD8（CD8A）、GZMB、CD20（MS4A1）、SDC1、PD-L1、ALOX5和TG2（TGM2）基因的高表达均与较差的OS相关。我们的数据揭示，5-LOX与GzmB的表达在RNA和蛋白水平上呈正相关，未来需要进一步研究5-LOX与免疫浸润在胶质瘤进展中的相互作用。

Primary malignant brain tumours are more than one-third of all brain tumours and despite the molecular investigation to identify cancer driver mutations, the current therapeutic options available are challenging due to high intratumour heterogeneity. In addition, an immunosuppressive and inflammatory tumour microenvironment strengthens cancer progression. Therefore, we defined an immune and inflammatory profiling of meningioma and glial tumours to elucidate the role of the immune infiltration in these cancer types.Using tissue microarrays of 158 brain tumour samples, we assessed CD3, CD4, CD8, CD20, CD138, Granzyme B (GzmB), 5-Lipoxygenase (5-LOX), Programmed Death-Ligand 1 (PD-L1), O-6-Methylguanine-DNA Methyltransferase (MGMT) and Transglutaminase 2 (TG2) expression by immunohistochemistry (IHC). IHC results were correlated using a Spearman correlation matrix. Transcript expression, correlation, and overall survival (OS) analyses were evaluated using public datasets available on GEPIA2 in Glioblastoma (GBM) and Lower Grade Glioma (LGG) cohorts.Seven out of ten markers showed a significantly different IHC expression in at least one of the evaluated cohorts whereas CD3, CD4 and 5-LOX were differentially expressed between GBMs and astrocytomas. Correlation matrix analysis revealed that 5-LOX and GzmB expression were associated in both meningiomas and GBMs, whereas 5-LOX expression was significantly and positively correlated to TG2 in both meningioma and astrocytoma cohorts. These findings were confirmed with the correlation analysis of TCGA-GBM and LGG datasets. Profiling of mRNA levels indicated a significant increase in CD3 (CD3D, CD3E), and CD138 (SDC1) expression in GBM compared to control tissues. CD4 and 5-LOX (ALOX5) mRNA levels were significantly more expressed in tumour samples than in normal tissues in both GBM and LGG. In GBM cohort, GzmB (GZMB), SDC1 and MGMT gene expression predicted a poor overall survival (OS). Moreover, in LGG cohort, an increased expression of CD3 (CD3D, CD3E, CD3G), CD8 (CD8A), GZMB, CD20 (MS4A1), SDC1, PD-L1, ALOX5, and TG2 (TGM2) genes was associated with worse OS.Our data have revealed that there is a positive and significant correlation between the expression of 5-LOX and GzmB, both at RNA and protein level. Further evaluation is needed to understand the interplay of 5-LOX and immune infiltration in glioma progression.