RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
吞噬作用在低级别胶质瘤中作用的生物信息学分析与实验验证
英文原题：Bioinformatics analyses and experimental validation of the role of phagocytosis in low-grade glioma.
查看英文原题
Bioinformatics analyses and experimental validation of the role of phagocytosis in low-grade glioma.
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研究概要
吞噬作用的分子特征得以揭示，PRPS 为 LGG 的个体化治疗奠定了基础。
中文摘要
背景
吞噬作用在肿瘤免疫应答中至关重要，但低级别胶质瘤（LGG）中吞噬作用的变化尚未得到研究。
方法
在泛癌范围内总结吞噬相关基因的mRNA、拷贝数变异、单核苷酸变异和甲基化水平。采用非负矩阵分解聚类鉴定两种LGG亚型；通过LASSO回归构建吞噬相关预后特征（PRPS）。进一步研究其免疫特征、免疫治疗应答和靶向药物敏感性。利用单细胞RNA测序（scRNA-seq）数据评估胶质瘤中的吞噬活性，并通过多重免疫组化（m-IHC）鉴定LGG中的肿瘤浸润免疫细胞。
结果
与相应正常组织相比，吞噬相关基因在多种癌症中明显改变。我们确定了两种LGG亚型，其中预后较差的亚型肿瘤纯度较低、免疫相关通路活性更高，CD4+ T细胞、CD8+ T细胞和自然杀伤（NK）细胞浸润增加，而巨噬细胞、肥大细胞和中性粒细胞浸润减少；该亚型还具有不同的通路活性和细胞死亡状态，对免疫治疗应答更好，并对环磷酰胺、厄洛替尼、吉非替尼、拉帕替尼和索拉非尼更敏感。此外，我们构建了由10个基因（SLC11A1、CAMK1D、PLA2G5、STAP1、ALOX15、PLCG2、SFTPD、AZU1、RAB27A和LAMTOR2）组成的PRPS，用于估算每个LGG样本的风险等级。高风险LGG患者预后较差，其肿瘤中中性粒细胞、巨噬细胞、Treg及髓系树突状细胞浸润上调，单核细胞和NK细胞浸润下调，且大量免疫检查点基因表达增加。单核细胞/巨噬细胞中的吞噬活性尤为显著。m-IHC结果证实，SLC11A1高表达LGG样本中巨噬细胞和中性粒细胞浸润增加。
结论
本研究揭示了吞噬作用的分子特征，并通过PRPS为LGG个体化治疗奠定了基础。
展开英文摘要原文
BACKGROUND
Phagocytosis is of vital importance in tumor immune response. The alteration of phagocytosis in low-grade glioma (LGG) has not been investigated.
METHODS
The mRNA, copy number variation, single nucleotide variation, and methylation levels of phagocytosis-related genes were summarized in pan-cancer. Non-negative matrix factorization clustering was utilized to identify two LGG subtypes. LASSO regression analysis was performed to construct a phagocytosis-related prognostic signature (PRPS). Immune characteristics, immunotherapy response, and targeted-drug sensitivity were further explored. The phagocytosis activity in glioma was evaluated using scRNA-seq data. Multiplex immunohistochemical (m-IHC) technology was performed to identify the tumor-infiltrating immune cells in LGG.
RESULTS
The phagocytosis-related genes altered obviously in pan-cancer compared with corresponding normal tissues. Two LGG subtypes were obtained and the subtype with poor prognosis was combined with lower tumor purity, more active immune-related pathways, increasing infiltration of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells, decreasing infiltration of macrophages, mast cells, and neutrophils, distinct pathway activity and cell death status, greater response to immunotherapy, and higher sensitivity to cyclophosphamide, erlotinib, gefitinib, lapatinib, and sorafenib. In addition, a PRPS involving 10 genes (i.e., SLC11A1, CAMK1D, PLA2G5, STAP1, ALOX15, PLCG2, SFTPD, AZU1, RAB27A, and LAMTOR2) was constructed to estimate the risk level of each LGG sample and high risk LGG patients had poor prognosis, upregulated infiltration of neutrophil, macrophage, Treg, and myeloid dendritic cell, down regulated infiltration of monocyte and NK cell, and increasing expression of large number of immune checkpoint genes. The phagocytosis activity is notably active in monocyte/macrophage. The m-IHC results confirmed increased infiltration of macrophages and neutrophils in LGG samples with high SLC11A1 expression.
CONCLUSION
The molecular characteristics of phagocytosis were revealed and the PRPS laid the foundation for personalized therapy in LGG.
论文信息
- 作者
- Fei M、Lu C、Feng B、Sun J、Wang J、Sun F、Dong B
- 单位
- Department of Neurosurgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.China
- 期刊
- Environmental toxicology2024 Apr
- 原文标识
- PubMed 38112449 · DOI 10.1002/tox.24095