Chen Zhen, Zhang Yongjun
Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China.
Department of Cardiothoracic Surgery, Xiangyang Central Hospital, Xiangyang, China.
PeerJ. 2025 May 8;13:e19121. doi: 10.7717/peerj.19121. eCollection 2025.
Lung adenocarcinoma (LUAD) is a major cause of cancer mortality. Considering the critical role of tumor infiltrating lymphocytes in effective immunotherapy, this study was designed to screen molecular markers related to tumor infiltrating cells in LUAD, aiming to improve immunotherapy response during LUAD therapy.
The ConsensusClusterPlus method was used for clustering immune molecular subtypes of LUAD. Immune cell infiltration and immunotherapeutic potential in each subtype was evaluated employing single-sample gene set enrichment analysis (ssGSEA), Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore (IPS). Immune-related co-expression modules were classified by weighted gene co-expression network analysis (WGCNA) analysis. The sequencing data of immune-related genes were comprehensively analyzed by introducing a new computational framework and 10 machine learning algorithms (a total of 101 combinations) to determine the prognostic genes, which were further combined to develop an immune prognostic signature (IMMPS) using the stepCox and Ridge methods. The expression of the signature genes was validated by quantitative real-time PCR (qRT-PCR).
Samples from The Cancer Genome Atlas dataset (TCGA-LUAD) were divided into two subtypes (immunosuppressive subgroup C1 and immune-activated subgroup C2); notably, the C2 subgroup was more likely to benefit from immunotherapy ( < 0.05). An IMMPS developed based on seven immune infiltrating cell-related genes (, and ) could accurately predict the overall survival of LUAD in five LUAD cohorts, with an average C-index higher than 0.69. LUAD patients with a low IMMPS value had a higher immune cell infiltration ( < 0.05). In addition, the IMMPS exhibited better prediction performance in comparison to 154 published gene signatures, suggesting that the IMMPS was an independent prognostic risk factor for evaluating the overall survival of LUAD patients. Since was the most relevant immune checkpoint gene, experiment showed that the expression of the seven key genes (, and ) in LUAD cell lines was consistent with that in normal lung epithelial cells after inhibiting expression ( < 0.05).
Our results contributed to a better understanding of immunological characteristics of LUAD. The IMMPS could serve as a promising tool for improving the clinical outcome of patients suffering from LUAD.
肺腺癌（LUAD）是癌症死亡的主要原因。鉴于肿瘤浸润淋巴细胞在有效免疫治疗中的关键作用，本研究旨在筛选与LUAD中肿瘤浸润细胞相关的分子标志物，以改善LUAD治疗期间的免疫治疗反应。
采用ConsensusClusterPlus方法对LUAD的免疫分子亚型进行聚类。采用单样本基因集富集分析（ssGSEA）、肿瘤免疫功能障碍与排除（TIDE）和免疫表型评分（IPS）评估各亚型中的免疫细胞浸润和免疫治疗潜力。通过加权基因共表达网络分析（WGCNA）分析对免疫相关共表达模块进行分类。通过引入一个新的计算框架和10种机器学习算法（共101种组合）对免疫相关基因的测序数据进行综合分析，以确定预后基因，并进一步结合使用stepCox和Ridge方法开发免疫预后特征（IMMPS）。通过定量实时PCR（qRT-PCR）验证特征基因的表达。
来自癌症基因组图谱数据集（TCGA-LUAD）的样本被分为两个亚型（免疫抑制亚组C1和免疫激活亚组C2）；值得注意的是，C2亚组更有可能从免疫治疗中获益（<0.05）。基于7个免疫浸润细胞相关基因（、和）开发的IMMPS能够准确预测5个LUAD队列中LUAD的总生存期，平均C指数高于0.69。IMMPS值低的LUAD患者免疫细胞浸润更高（<0.05）。此外，与154个已发表的基因特征相比，IMMPS表现出更好的预测性能，表明IMMPS是评估LUAD患者总生存期的独立预后危险因素。由于是最相关的免疫检查点基因，实验表明，在抑制表达后，LUAD细胞系中7个关键基因（、和）的表达与正常肺上皮细胞中的表达一致（<0.05）。
我们的结果有助于更好地理解LUAD的免疫特征。IMMPS可作为改善LUAD患者临床结局的有前景的工具。
