LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p< 0.0001), 8.9-fold (p< 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase,p< 0.0001) and TGFB2 (2.2-fold increase,p< 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p< 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2highHR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation inTGFB2,IFNGR2,IRF1,IRF5,STAT1, andCD276were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes.
低级别胶质瘤（LGG）肿瘤的特征是免疫细胞浸润程度较低，因此需要治疗干预以增强免疫应答。我们开展了一项研究，分析了来自UCSC Xena网络平台的mRNA表达数据集。为了筛选上调基因，我们试图比较正常脑组织与LGG肿瘤样本。我们还利用cBioportal平台确定了513名LGG患者的mRNA表达水平与其总生存期（OS）结果之间的关系。在LGG肿瘤中，三种肿瘤相关巨噬细胞（TAM）标志物MSR1/CD204、CD86和CD68的mRNA表达水平分别显示出6倍（p<0.0001）、8.9倍（p<0.0001）和15.6倍（p<0.0001）的增加。此外，与正常脑组织相比，这些肿瘤中TGFB1（4.1倍增加，p<0.0001）和TGFB2（2.2倍增加，p<0.0001）配体也均上调，这表明TGFB配体在通过TAM介导的胶质瘤免疫抑制、促血管生成和促肿瘤发生的肿瘤微环境（TME）建立中起关键作用。同时，干扰素-γ受体IFNGR1和IFNGR2以及下游信号分子STAT1、IRF1和IRF5的mRNA上调，指出了IFN-γ介导的TME重塑的重要作用。有趣的是，肿瘤相关抗原CD276/B7-H3的mRNA表达在肿瘤组织中显示出显著（p<0.0001）的4.03倍增加，这进一步揭示了巨噬细胞和肿瘤细胞在支持免疫抑制性TME中的作用。研究TGFB2与IFNGR2、STAT1、IRF1或IRF5激活相互作用的多变量Cox比例风险模型显示，高mRNA水平（以第25百分位为截断值）的TGFB2的预后影响独立于IFNGR2、STAT1、IRF1或IRF5的mRNA水平（在分别包含IFNGR2、STAT1、IRF1或IRF5的模型中，TGFB2高表达的HR（95% CI）分别为4.07（2.35–7.06）、6（3.62–10.11）、4.38（2.67–7.17）和4.48（2.82–7.12））以及诊断年龄。高水平TGFB2和IFNGR2的患者在异柠檬酸脱氢酶野生型（IDHwt）突变状态的LGG患者中比例过高。通过TGFB2（HR（95% CI范围）= 2.02（1.05–3.89））和IDH野生型（HR（95% CI范围）= 4.44（1.9–10.4））风险比的增加观察到的高水平TGFB2和IDH野生型的预后影响是生存的独立预测因素，这表明在临床试验设计中，对患者进行风险分层可以识别出IDH野生型且TGFB2水平高的LGG患者。此外，我们还补充了IRF5和CD276/B7-H3作为预后标志物，这些标志物也可以作为与TGFB2抑制剂联合治疗的靶点。为了支持这些发现，我们证明了TGFB2、IFNGR2、IRF1、IRF5、STAT1和CD276的低水平基因甲基化与显著更差的总生存期（OS）结果相关。这表明增加这些预后标志物表达的潜在机制可能是通过去甲基化酶的作用实现的。
肿瘤(癌症)患者之家