Luo Yuqi, Lu Caijie, Huang Yiwen, Liao Weihua, Huang Yaoxing
Department of Gastrointestinal and Hepatobiliary Surgery, Shenzhen Longhua District Central Hospital, No. 187, Guanlan Road, Longhua District, Shenzhen 518110, Guangdong Province, China.
Department of Emergency, Nansha Hospital, Guangzhou First People's Hospital, School of Medicine, Southern China University of Technology, Guangzhou, Guangdong, China.
Heliyon. 2024 Jun 7;10(12):e32531. doi: 10.1016/j.heliyon.2024.e32531. eCollection 2024 Jun 30.
Colon adenocarcinoma (COAD) is a serious public health issue due to high incidence and mortality rate. This study aimed to identify possible tumor antigens and necroptosis subtypes of COAD for the development of mRNA vaccines and the selection of appropriate patients for precision therapy.
Gene expression profiles and clinical information for COAD were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, respectively. We comprehensively studied the alterations in necroptosis-related genes (NRGs) using cBioPortal, and screened the hub NRGs associated with the prognosis of patients with COAD using Gene Expression Profiling Interactive Analysis 2. Consensuses clustering analysis was performed to identify necroptosis subtypes. Weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules of the NRGs. The necroptosis landscape of COAD was assessed using graph learning-based dimensionality reduction. Finally, a drug sensitivity analysis of the two necroptosis subtypes was performed.
Two tumor antigens, BLC-2-associated X protein (BAX) and interleukin 1 beta (IL1B) were identified based on their associations with prognosis of patients and antigen presenting cell infiltration. Two necroptosis subtypes (N1 and N2) were distinguished in patients with COAD, and they were characterized by their differential survival status and molecular expression levels of immune checkpoint proteins and immunogenetic cell death modulators. Furthermore, the necroptosis landscape of COAD indicated that individual patients had obvious heterogeneity. Co-expression modules were identified using WGCNA, and the hub NRGs were found to be involved in various immune processes. Drug sensitivity analysis indicated that there were significant differences in drug sensitivity between the N1 and N2 subtypes. Cell experiments suggested that both overexpression of BAX and IL1B promoted necroptosis of COAD cells and enhanced the cytotoxicity of CD8 T cells.
BAX and IL1B are potential antigens for the development of anti-COAD mRNA vaccines, specifically for patients with the N2 subtype. Consequently, this study will guide the development of more effective immunotherapeutic approaches and the identification of appropriate patients.
由于高发病率和死亡率，结肠腺癌（COAD）是一个严重的公共卫生问题。本研究旨在确定COAD可能的肿瘤抗原和坏死性凋亡亚型，以开发mRNA疫苗并为精准治疗选择合适的患者。
分别从癌症基因组图谱（The Cancer Genome Atlas）和基因表达综合数据库（Gene Expression Omnibus）获取COAD的基因表达谱和临床信息。我们使用cBioPortal全面研究坏死性凋亡相关基因（NRGs）的改变，并使用基因表达谱交互式分析2（Gene Expression Profiling Interactive Analysis 2）筛选与COAD患者预后相关的核心NRGs。进行共识聚类分析以识别坏死性凋亡亚型。使用加权基因共表达网络分析（WGCNA）识别NRGs的共表达模块。使用基于图学习的降维方法评估COAD的坏死性凋亡格局。最后，对两种坏死性凋亡亚型进行药物敏感性分析。
基于与患者预后和抗原呈递细胞浸润的关联，确定了两种肿瘤抗原，即B淋巴细胞瘤-2相关X蛋白（BAX）和白细胞介素1β（IL1B）。在COAD患者中区分出两种坏死性凋亡亚型（N1和N2），其特征在于不同的生存状态以及免疫检查点蛋白和免疫原性细胞死亡调节剂的分子表达水平。此外，COAD的坏死性凋亡格局表明个体患者具有明显的异质性。使用WGCNA识别共表达模块，发现核心NRGs参与各种免疫过程。药物敏感性分析表明N1和N2亚型之间的药物敏感性存在显著差异。细胞实验表明，BAX和IL1B的过表达均促进COAD细胞坏死性凋亡并增强CD8 T细胞的细胞毒性。
BAX和IL1B是开发抗COAD mRNA疫苗的潜在抗原，特别是对于N2亚型患者。因此，本研究将指导开发更有效的免疫治疗方法并识别合适的患者。
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