Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
National Center for Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
J Cancer Res Clin Oncol. 2024 May 9;150(5):246. doi: 10.1007/s00432-024-05774-7.
Recent studies have emphasized the importance of the biological processes of different forms of cell death in tumor heterogeneity and anti-tumor immunity. Nonetheless, the relationship between cuproptosis and lung adenocarcinoma (LUAD) remains largely unexplored.
Data for 793 LUAD samples and 59 normal lung tissues obtained from TCGA-LUAD cohort GEO datasets were used in this study. A total of 165 LUAD tissue samples and paired normal lung tissue samples obtained from our hospital were used to verify the prognostic value of dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide branched chain transacylase E2 (DBT) for LUAD. The cuproptosis-related molecular patterns of LUAD were identified using consensus molecular clustering. Recursive feature elimination with random forest and a tenfold cross-validation method was applied to construct the cuproptosis score (CPS) for LUAD.
Bioinformatic and immunohistochemistry (IHC) analyses revealed that 13 core genes of cuproptosis were all significantly elevated in LUAD tissues, among which DBT and DLAT were associated with poor prognosis (DLAT, HR = 6.103; DBT, HR = 4.985). Based on the expression pattern of the 13 genes, two distinct cuproptosis-related patterns have been observed in LUAD: cluster 2 which has a relatively higher level of cuproptosis was characterized by immunological ignorance; conversely, cluster 1 which has a relatively lower level of cuproptosis is characterized by TILs infiltration and anti-tumor response. Finally, a scoring scheme termed the CPS was established to quantify the cuproptosis-related pattern and predict the prognosis and the response to immune checkpoint blockers of each individual patient with LUAD.
Cuproptosis was found to influence tumor microenvironment (TME) characteristics and heterogeneity in LUAD. Patients with a lower CPS had a relatively better prognosis, more abundant immune infiltration in the TME, and an enhanced response to immune checkpoint inhibitors.
最近的研究强调了不同形式的细胞死亡的生物学过程在肿瘤异质性和抗肿瘤免疫中的重要性。然而，铜死亡与肺腺癌（LUAD）之间的关系在很大程度上仍未得到探索。
本研究使用来自 TCGA-LUAD 队列 GEO 数据集的 793 个 LUAD 样本和 59 个正常肺组织的数据。从我们医院获得的总共 165 个 LUAD 组织样本和配对的正常肺组织样本用于验证二氢乳清酸 S-乙酰转移酶（DLAT）和二氢乳清酸支链转酰酶 E2（DBT）对 LUAD 的预后价值。使用共识分子聚类鉴定 LUAD 的铜死亡相关分子模式。应用递归特征消除与随机森林和十折交叉验证方法构建 LUAD 的铜死亡评分（CPS）。
生物信息学和免疫组织化学（IHC）分析表明，LUAD 组织中 13 个铜死亡核心基因均显著升高，其中 DBT 和 DLAT 与预后不良相关（DLAT，HR=6.103；DBT，HR=4.985）。基于 13 个基因的表达模式，在 LUAD 中观察到两种不同的铜死亡相关模式：簇 2 具有相对较高的铜死亡水平，其特征是免疫忽视；相反，簇 1 具有相对较低的铜死亡水平，其特征是 TILs 浸润和抗肿瘤反应。最后，建立了一种评分方案，称为 CPS，用于量化铜死亡相关模式，并预测每个 LUAD 患者的预后和对免疫检查点抑制剂的反应。
在 LUAD 中，铜死亡被发现影响肿瘤微环境（TME）的特征和异质性。CPS 较低的患者预后相对较好，TME 中免疫浸润较多，对免疫检查点抑制剂的反应增强。
