Li Wei, Zhang Xingda, Chen Yanbo, Pang Da
Harbin Medical University Cancer Hospital, Harbin, China.
Heilongjiang Academy of Medical Sciences, Harbin, China.
Front Oncol. 2022 Sep 23;12:966511. doi: 10.3389/fonc.2022.966511. eCollection 2022.
Cuproptosis, a recently discovered refreshing form of cell death, is distinct from other known mechanisms. As copper participates in cell death, the induction of cancer cell death with copper ionophores may emerge as a new avenue for cancer treatment. However, the role of cuproptosis in tumor microenvironment (TME) cell infiltration remains unknown.
We systematically evaluated the cuproptosis patterns in The Cancer Genome Atlas (TCGA) database in breast cancer (BRCA) samples based on 10 cuproptosis-related genes (CRGs), and correlated these patterns with the prognosis and characteristics of TME cell infiltration. A principal component analysis algorithm was used to construct a cuproptosis score to quantify the cuproptosis pattern in individual tumors. Further, the relationships between the cuproptosis score and transcription background, clinical features, characteristics of TME cell infiltration, drug response, and efficacy of immunotherapy were assessed.
Two distinct cuproptosis patterns with distinct prognoses were identified; their TME characteristics were found to be consistent with the immune-excluded and immune-inflamed phenotypes, respectively. The cuproptosis patterns in individual patients were evaluated using the cuproptosis score based on the cuproptosis phenotype-related genes, contributing to distinguishing biological processes, clinical outcome, immune cell infiltration, genetic variation, and drug response. Univariate and multivariate Cox regression analyses verified this score as an independent prognostic predictor in BRCA. A high cuproptosis score, characterized by immune activation, suggests an inflamed tumor and immune-inflamed phenotype with poor survival and a low cuproptosis score, characterized by immune suppression, indicates a non-inflamed tumor and immune-excluded phenotype with better survival. Significant differences were observed in the IC50 between the high and low cuproptosis score groups receiving chemotherapy and targeted therapy drugs. In the two immunotherapy cohorts, patients with a higher cuproptosis score experienced considerable therapeutic advantages and clinical benefits.
This study is the first to elucidate the prominent role of cuproptosis in the clinical outcome and the formation of TME diversity and complexity in BRCA. Estimating cuproptosis patterns in tumors could help predict the prognosis and characteristics of TME cell infiltration and guide more effective chemotherapeutic and immunotherapeutic strategies.
铜死亡是一种最近发现的全新细胞死亡形式，与其他已知机制不同。由于铜参与细胞死亡，利用铜离子载体诱导癌细胞死亡可能成为癌症治疗的新途径。然而，铜死亡在肿瘤微环境（TME）细胞浸润中的作用尚不清楚。
我们基于10个铜死亡相关基因（CRG），系统评估了癌症基因组图谱（TCGA）数据库中乳腺癌（BRCA）样本的铜死亡模式，并将这些模式与TME细胞浸润的预后和特征相关联。使用主成分分析算法构建铜死亡评分，以量化个体肿瘤中的铜死亡模式。此外，还评估了铜死亡评分与转录背景、临床特征、TME细胞浸润特征、药物反应和免疫治疗疗效之间的关系。
识别出两种具有不同预后的不同铜死亡模式；发现它们的TME特征分别与免疫排除和免疫炎症表型一致。使用基于铜死亡表型相关基因的铜死亡评分评估个体患者的铜死亡模式，有助于区分生物学过程、临床结果、免疫细胞浸润、基因变异和药物反应。单因素和多因素Cox回归分析证实该评分是BRCA的独立预后预测指标。高铜死亡评分以免疫激活为特征，提示肿瘤炎症和免疫炎症表型，生存率低；低铜死亡评分以免疫抑制为特征，表明肿瘤无炎症和免疫排除表型，生存率高。接受化疗和靶向治疗药物的高铜死亡评分组和低铜死亡评分组之间的半数抑制浓度（IC50）存在显著差异。在两个免疫治疗队列中，铜死亡评分较高的患者具有显著的治疗优势和临床益处。
本研究首次阐明了铜死亡在BRCA临床结果以及TME多样性和复杂性形成中的重要作用。评估肿瘤中的铜死亡模式有助于预测TME细胞浸润的预后和特征，并指导更有效的化疗和免疫治疗策略。
