Sheng Haoyue, Gu Jiani, Huang Yongqiang, Kołat Damian, Shi Guohai, Yan Lihua, Ye Dingwei
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Transl Androl Urol. 2024 Oct 31;13(10):2280-2293. doi: 10.21037/tau-24-456. Epub 2024 Oct 28.
Cuproptosis is a newly identified form of cell death that is dependent on copper (Cu) ions, termed Cu-dependent cytotoxicity. This process is distinct from other forms of cell death such as apoptosis, necrosis, and ferroptosis. The accumulation of copper is known to play a significant role in various biological processes, including angiogenesis (the formation of new blood vessels) and metastasis (the spread of cancer cells to different parts of the body). These processes are crucial for tumor growth and progression, indicating that copper and the cuproptosis-related genes (CPRGs) might be indispensable in the context of cancer development and progression. Given this background, we aimed to explore the relationship between CPRGs and both prognostic predictions and tumor microenvironment (TME) infiltration in bladder cancer (BLCA).
For this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify CPRGs and subsequently divided BLCA patients into three distinct molecular clusters based on these genes. To assess the proportions of various immune cell types within the TME, we employed single-sample gene set enrichment analysis (ssGSEA) and the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) method. These computational techniques allowed us to quantify the infiltration of different immune cells, providing insights into the immune landscape of the tumors. Furthermore, we developed a risk score model using CPRGs to predict the survival prospects of BLCA patients.
Our analysis identified three molecular clusters of BLCA patients, each exhibiting unique clinical features and patterns of TME infiltration. Among these clusters, cluster 1 was associated with a poor prognosis. Interestingly, this cluster also showed significant infiltration of activated CD4 (ssGSEA P<0.001) and CD8 T (ssGSEA P<0.05) cells, which are crucial components of the immune response against tumors. This finding suggests a complex interaction between the immune system and the tumor, where a high presence of T cells does not necessarily correlate with better outcomes. Additionally, our risk score model revealed that the high-risk group, characterized by a specific expression pattern of CPRGs, also had enhanced infiltration of CD4 and CD8 T cells. This indicates that the cuproptosis-based risk model has a robust ability to predict patient prognosis and can guide immunotherapy decisions.
Our study sheds light on the biological functions of CPRGs within the TME of BLCA and their correlations with clinical parameters and patient prognosis. The identification of distinct molecular clusters with varying prognoses and immune cell infiltrations highlights the heterogeneity of BLCA and underscores the potential of CPRGs as biomarkers for prognosis and therapeutic targets. These findings offer new perspectives for the development of immunotherapeutic strategies in the treatment of BLCA patients, potentially leading to more personalized and effective cancer therapies.
铜死亡是一种新发现的细胞死亡形式，依赖于铜离子，称为铜依赖性细胞毒性。这个过程不同于其他形式的细胞死亡，如凋亡、坏死和铁死亡。已知铜的积累在各种生物学过程中发挥重要作用，包括血管生成（新血管的形成）和转移（癌细胞扩散到身体的不同部位）。这些过程对肿瘤的生长和进展至关重要，这表明铜和铜死亡相关基因（CPRGs）在癌症发展和进展过程中可能是不可或缺的。基于此背景，我们旨在探讨CPRGs与膀胱癌（BLCA）的预后预测和肿瘤微环境（TME）浸润之间的关系。
在本研究中，我们利用来自癌症基因组图谱（TCGA）的数据来识别CPRGs，并随后根据这些基因将BLCA患者分为三个不同的分子簇。为了评估TME中各种免疫细胞类型的比例，我们采用了单样本基因集富集分析（ssGSEA）和通过估计RNA转录本相对子集进行细胞类型鉴定（CIBERSORT）方法。这些计算技术使我们能够量化不同免疫细胞的浸润情况，从而深入了解肿瘤的免疫格局。此外，我们利用CPRGs开发了一个风险评分模型，以预测BLCA患者的生存前景。
我们的分析确定了BLCA患者的三个分子簇，每个簇都表现出独特的临床特征和TME浸润模式。在这些簇中，簇1与预后不良相关。有趣的是，这个簇还显示出活化的CD4（ssGSEA P<0.001）和CD8 T（ssGSEA P<0.05）细胞的显著浸润，这些细胞是抗肿瘤免疫反应的关键组成部分。这一发现表明免疫系统与肿瘤之间存在复杂的相互作用，其中T细胞的高存在并不一定与更好的结果相关。此外，我们的风险评分模型显示，以CPRGs的特定表达模式为特征的高危组也有CD4和CD8 T细胞浸润增强。这表明基于铜死亡的风险模型具有强大的预测患者预后的能力，并可指导免疫治疗决策。
我们的研究揭示了CPRGs在BLCA的TME中的生物学功能及其与临床参数和患者预后的相关性。具有不同预后和免疫细胞浸润的不同分子簇的识别突出了BLCA的异质性，并强调了CPRGs作为预后生物标志物和治疗靶点的潜力。这些发现为BLCA患者免疫治疗策略的开发提供了新的视角，可能导致更个性化和有效的癌症治疗。
