Qazi Sanjive, Talebi Zahra, Trieu Vuong
Oncotelic Therapeutics, 29397 Agoura Road, Suite 107, Agoura Hills, CA 91301, USA.
Biomedicines. 2024 Jan 15;12(1):191. doi: 10.3390/biomedicines12010191.
This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold ( = 0.037), 1.75-fold ( = 0.019), and 3.33-fold ( < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase ( = 0.002) and 1.58-fold increase ( = 5.5 × 10), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2 group of pbDMG patients = 2.88 (1.12-7.39); = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 ( = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.
这项产生假设的研究对小儿脑干弥漫性中线胶质瘤（pbDMG）肿瘤中抗原呈递细胞（APC）标志物（CD14、CD163、CD86和ITGAX/CD11c）的mRNA表达谱及其预后影响进行了特征分析。我们还评估了两个治疗靶点——转化生长因子β2（TGFB2）和干扰素γ受体2（IFNGR2）在这些高度侵袭性pbDMG肿瘤中的生物标志物潜力。与正常脑干/脑桥样本相比，pbDMG肿瘤中CD14、CD163和ITGAX/CD11c mRNA的表达分别显著降低了1.64倍（P = 0.037）、1.75倍（P = 0.019）和3.33倍（P < 0.0001）。TGFB2水平高且APC标志物水平低的pbDMG样本反映了pbDMG肿瘤的冷免疫状态，在CD14、CD163和CD86低表达水平时，其总生存结果显著更差。与正常脑干/脑桥样本相比，pbDMG肿瘤中IFNGR2和TGFB2的表达水平（分别增加1.51倍（P = 0.002）和1.58倍（P = 5.5×10））显著上调。我们进行了多变量Cox比例风险模型分析，结果显示TGFB2是总生存（OS）不良的预后指标（pbDMG患者TGFB2组患者的风险比 = 2.88（1.12 - 7.39）；P = 0.028），且独立于IFNGR2水平、患者年龄以及IFNGR2与TGFB2之间观察到的显著交互作用（P = 0.015）。在IFNGR2水平低的情况下，比较高TGFB2水平与低TGFB2水平时，pbDMG患者生存结果更差，这表明在免疫冷肿瘤微环境中消除TGFB2 mRNA表达可用于治疗pbDMG患者。此外，JAK1或STAT1 mRNA表达水平低且TGFB2水平高的pbDMG患者也表现出不良的OS结果，这表明在脑干肿瘤微环境中加入（干扰素 - γ）IFN - γ以刺激和激活抗肿瘤APC细胞中的JAK1和STAT1可以增强TGFB2阻断的效果。
