Table_2_Effects of 1p/19q Codeletion on Immune Phenotype in Low Grade Glioma.XLSX

Background: Chromosome 1p/19q codeletion is one of the most important genetic alterations for low grade gliomas (LGGs), and patients with 1p/19q codeletion have significantly prolonged survival compared to those without the codeletion. And the tumor immune microenvironment also plays a vital role in the tumor progression and prognosis. However, the effect of 1p/19q codeletion on the tumor immune microenvironment in LGGs is unclear.
Methods: Immune cell infiltration of 281 LGGs from The Cancer Genome Atlas (TCGA) and 543 LGGs from the Chinese Glioma Genome Atlas (CGGA) were analyzed for immune cell infiltration through three bioinformatics tools: ESTIMATE algorithm, TIMER, and xCell. The infiltrating level of immune cells and expression of immune checkpoint genes were compared between different groups classified by 1p/19q codeletion and IDH (isocitrate dehydrogenase) mutation status. The differential biological processes and signaling pathways were evaluated through Gene Set Enrichment Analysis (GSEA). Correlations were analyzed using Spearman correlation.
Results: 1p/19q codeletion was associated with immune-related biological processes in LGGs. The infiltrating level of multiple kinds of immune cells and expression of immune checkpoint genes were significantly lower in 1p/19q codeletion LGGs compared to 1p/19q non-codeletion cohorts. There are 127 immune-related genes on chromosome 1p or 19q, such as TGFB1, JAK1, and CSF1. The mRNA expression of these genes was positively correlated with their DNA copy number. These genes are distributed in multiple immune categories, such as chemokines/cytokines, TGF-β family members, and TNF family members, regulating immune cell infiltration and expression of the immune checkpoint genes in tumors.
Conclusion: Our results indicated that 1p/19q codeletion status is closely associated with the immunosuppressive microenvironment in LGGs. LGGs with 1p/19q codeletion display less immune cell infiltration and lower expression of immune checkpoint genes than 1p/19q non-codeletion cases. Mechanistically, this may be, at least in part, due to the deletion of copy number of immune-related genes in LGGs with 1p/19q codeletion. Our findings may be relevant to investigate immune evasion in LGGs and contribute to the design of immunotherapeutic strategies for patients with LGGs.

背景：染色体1p/19q共缺失是低级别胶质瘤（low grade gliomas, LGG）最重要的遗传改变之一，携带1p/19q共缺失的患者相较于无该缺失的患者，生存期显著延长。肿瘤免疫微环境在肿瘤进展与预后中同样发挥关键作用，但1p/19q共缺失对低级别胶质瘤肿瘤免疫微环境的影响尚不明确。
方法：本研究通过三种生物信息学工具——ESTIMATE算法、TIMER及xCell，对来自癌症基因组图谱（The Cancer Genome Atlas, TCGA）的281例低级别胶质瘤样本，以及来自中国胶质瘤基因组图谱（Chinese Glioma Genome Atlas, CGGA）的543例低级别胶质瘤样本的免疫细胞浸润情况进行分析。依据1p/19q共缺失与异柠檬酸脱氢酶（isocitrate dehydrogenase, IDH）突变状态对样本进行分组，比较不同组间免疫细胞浸润水平与免疫检查点基因的表达差异。通过基因集富集分析（Gene Set Enrichment Analysis, GSEA）评估差异生物学过程与信号通路，并采用斯皮尔曼相关性分析探究变量间关联。
结果：研究发现，1p/19q共缺失与低级别胶质瘤内的免疫相关生物学过程密切相关。相较于1p/19q非共缺失队列，携带1p/19q共缺失的低级别胶质瘤样本中，多种免疫细胞的浸润水平与免疫检查点基因的表达均显著降低。染色体1p或19q上共存在127个免疫相关基因，例如TGFB1、JAK1及CSF1。这些基因的mRNA表达水平与其DNA拷贝数呈正相关。它们可分为趋化因子/细胞因子、转化生长因子-β（transforming growth factor-β, TGF-β）家族成员、肿瘤坏死因子（Tumor Necrosis Factor, TNF）家族成员等多个免疫相关类别，可调控肿瘤内免疫细胞浸润与免疫检查点基因的表达。
结论：本研究结果表明，1p/19q共缺失状态与低级别胶质瘤的免疫抑制微环境密切相关。相较于1p/19q非共缺失病例，携带1p/19q共缺失的低级别胶质瘤表现出更低的免疫细胞浸润水平与免疫检查点基因表达。从机制上而言，这至少部分归因于携带1p/19q共缺失的低级别胶质瘤中免疫相关基因的拷贝数缺失。本研究结果可为低级别胶质瘤免疫逃逸机制的探究提供参考，并有助于低级别胶质瘤患者免疫治疗策略的设计。