APOBEC3C is a novel target for the immune treatment of lower-grade gliomas

Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C (A3C) has been identified as a cancer molecular biomarker in the past decade. However, the practical role of A3C in lower-grade gliomas (LGGs) in improving the clinical outcome remains unclear. This study aims to discuss the function of A3C in immunotherapy in LGGs. The RNA-Sequencing (RNA-seq) and corresponding clinical data were extracted from UCSC Xena and the results were verified in the Chinese Glioma Genome Atlas (CGGA). Weighted gene co-expression network analysis (WGCNA) was used for screening A3C-related genes. Comprehensive bioinformation analyses were performed and multiple levels of expression, survival rate, and biological functions were assessed to explore the functions of A3C. A3C expression was significantly higher in LGGs than in normal tissues but lower than in glioblastoma (GBM), indicating its role as an independent prognosis predictor for LGGs. Twenty-eight A3C-related genes were found with WGCNA for unsupervised clustering analysis and three modification patterns with different outcomes and immune cell infiltration were identified. A3C and the A3C score were also correlated with immune cell infiltration and the expression of immune checkpoints. In addition, the A3C score was correlated with increased sensitivity to chemotherapy. Single-cell RNA (scRNA) analysis indicated that A3C most probably expresses on immune cells, such as T cells, B cells and macrophage. A3C is an immune-related prognostic biomarker in LGGs. Developing drugs to block A3C could enhance the efficiency of immunotherapy and improve disease survival. <b>Abbreviation:</b> A3C: Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C; LGGs: lower-grade gliomas; CGGA: Chinese Glioma Genome Atlas; WGCNA: Weighted gene co-expression network analysis; scRNA: Single-cell RNA; HGG: higher-grade glioma; OS: overall survival; TME: tumor microenvironment; KM: Kaplan-Meier; PFI: progression-free interval; IDH: isocitrate dehydrogenase; ROC: receiver operating characteristic; GS: gene significance; MM: module membership; TIMER: Tumor IMmune Estimation Resource; GSVA: gene set variation analysis; ssGSEA: single-sample gene-set enrichment analysis; PCA: principal component analysis; AUC: area under ROC curve; HAVCR2: hepatitis A virus cellular receptor 2; PDCD1: programmed cell death 1; PDCD1LG2: PDCD1 ligand 2; PTPRC: protein tyrosine phosphatase receptor type C; ACC: Adrenocortical carcinoma; BLCA: Bladder Urothelial Carcinoma;BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOLCholangiocarcinoma; COADColon adenocarcinoma; DLBC: Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; HNSC: Head and Neck squamous cell carcinoma; KICH: Kidney Chromophobe; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LAML: Acute Myeloid Leukemia; LGG: Brain Lower Grade Glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; MESO: Mesothelioma; OV: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SARC: Sarcoma; SKCM: Skin Cutaneous Melanoma; STAD: Stomach adenocarcinoma; TGCT: Testicular Germ Cell Tumors; THCA: Thyroid carcinoma; THYM: Thymoma; UCEC: Uterine Corpus Endometrial Carcinoma; UCS: Uterine Carcinosarcoma; UVM: Uveal Melanoma

近十年来，载脂蛋白B mRNA编辑催化多肽样（APOBEC）3型C（A3C）已被确定为癌症分子生物标志物。然而，A3C在低级别胶质瘤（LGGs）中对改善临床结局的实际作用仍不明确。本研究旨在探讨A3C在低级别胶质瘤免疫治疗中的功能。本研究从UCSC Xena数据库提取了RNA测序（RNA-seq）及对应临床数据，并在中国胶质瘤基因组图谱（CGGA）中对结果进行了验证。采用加权基因共表达网络分析（WGCNA）筛选A3C相关基因，通过多维度生物信息学分析，从表达水平、生存率及生物学功能等多个层面展开评估，以探究A3C的功能。研究结果显示，A3C在低级别胶质瘤组织中的表达显著高于正常组织，但低于胶质母细胞瘤（GBM），表明其可作为低级别胶质瘤的独立预后预测因子。通过WGCNA共筛选得到28个A3C相关基因，经无监督聚类分析后，鉴定出三种具有不同临床结局和免疫细胞浸润特征的修饰模式。A3C及其评分与免疫细胞浸润及免疫检查点基因的表达均存在相关性。此外，A3C评分还与化疗敏感性升高相关。单细胞RNA（scRNA）分析表明，A3C最有可能在T细胞、B细胞及巨噬细胞等免疫细胞中表达。A3C是低级别胶质瘤中一种免疫相关的预后生物标志物。开发靶向阻断A3C的药物，有望增强免疫治疗效率并改善患者疾病生存预后。<b>缩写：</b>A3C: 载脂蛋白B mRNA编辑催化多肽样（APOBEC）3型C；LGGs: 低级别胶质瘤；CGGA: 中国胶质瘤基因组图谱；WGCNA: 加权基因共表达网络分析；scRNA: 单细胞RNA；HGG: 高级别胶质瘤；OS: 总生存期；TME: 肿瘤微环境；KM: 卡普兰-迈耶法；PFI: 无进展间期；IDH: 异柠檬酸脱氢酶；ROC: 受试者工作特征；GS: 基因显著性；MM: 模块成员性；TIMER: 肿瘤免疫估算资源；GSVA: 基因集变异分析；ssGSEA: 单样本基因集富集分析；PCA: 主成分分析；AUC: ROC曲线下面积；HAVCR2: 甲型肝炎病毒细胞受体2；PDCD1: 程序性细胞死亡蛋白1；PDCD1LG2: 程序性细胞死亡蛋白1配体2；PTPRC: 蛋白酪氨酸磷酸酶受体类型C；ACC: 肾上腺皮质癌；BLCA: 膀胱尿路上皮癌；BRCA: 浸润性乳腺癌；CESC: 宫颈鳞状细胞癌及宫颈内膜腺癌；CHOL: 胆管癌；COAD: 结肠腺癌；DLBC: 弥漫大B细胞淋巴瘤；ESCA: 食管癌；GBM: 多形性胶质母细胞瘤；HNSC: 头颈部鳞状细胞癌；KICH: 肾嫌色细胞癌；KIRC: 肾透明细胞癌；KIRP: 肾乳头状细胞癌；LAML: 急性髓系白血病；LGG: 脑低级别胶质瘤；LIHC: 肝细胞癌；LUAD: 肺腺癌；LUSC: 肺鳞状细胞癌；MESO: 间皮瘤；OV: 卵巢浆液性囊腺癌；PAAD: 胰腺腺癌；PCPG: 嗜铬细胞瘤及副神经节瘤；PRAD: 前列腺腺癌；READ: 直肠腺癌；SARC: 肉瘤；SKCM: 皮肤黑色素瘤；STAD: 胃腺癌；TGCT: 睾丸生殖细胞肿瘤；THCA: 甲状腺癌；THYM: 胸腺瘤；UCEC: 子宫体子宫内膜癌；UCS: 子宫癌肉瘤；UVM: 葡萄膜黑色素瘤