Development and validation of cuproptosis-related lncRNAs associated with pancreatic cancer immune microenvironment based on single-cell

Frontiers in Immunology

Immunology

Rong He¹  Yimeng Sun¹  Changfeng Man¹  Yu Fan¹  Lin Yao¹  Zhenjun Gao² 

[1] Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China;Department of Gastroenterology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China;

关键词: cuproptosis;    single-cell sequence;    immunotherapy;    tumor immune microenvironment;    pancreatic cancer;    prognostic signature;   

DOI  :  10.3389/fimmu.2023.1220760

 received in 2023-05-11, accepted in 2023-09-12,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundCuproptosis, a novel mode of cell death associated with the tricarboxylic acid (TCA) cycle, is relevant to the development of cancer. However, the impact of single-cell-based Cuproptosis-associated lncRNAs on the Tumor immune microenvironment (TIME) of Pancreatic adenocarcinoma (PAAD) and its potential value for individualized immunotherapy has not been clarified.Methods14 immune-related CRGs were screened by exploring the interaction between differentially expressed Immune-Related Genes (IRGs) and Cuproptosis-Related Genes (CRGs) in PAAD. Next, the expression amount and expression distribution of CRGs in single-cell samples were analyzed by focusing on 7-CRGs with significant expressions. On the one hand, MAP2K2, SOD1, and VEGFA, which were significantly differentially expressed between PAAD sites and normal tissues adjacent to them, were subjected to immunohistochemical validation and immune landscape analysis. On the other hand, from these 7-CRGs, prognostic signatures of lncRNAs were established by co-expression and LASSO-COX regression analysis, and their prognostic value and immune relevance were assessed. In addition, this study not only validated the hub CRGs and the lncRNAs constituting the signature in a PAAD animal model treated with immunotherapy-based combination therapy using immunohistochemistry and qRT-PCR but also explored the potential value of the combination of targeted, chemotherapy and immunotherapy.ResultsBased on the screening of 7-CRGs significantly expressed in a PAAD single-cell cohort and their co-expressed Cuproptosis-Related lncRNAs (CRIs), this study constructed a prognostic signature of 4-CRIs named CIR-score. A Nomogram integrating the CIR-score and clinical risk factors was constructed on this basis to predict the individualized survival of patients. Moreover, high and low-risk groups classified according to the median of signatures exhibited significant differences in clinical prognosis, immune landscape, bioenrichment, tumor burden, and drug sensitivity. And the immunohistochemical and qRT-PCR results of different mouse PAAD treatment strategies were consistent with the trend of inter-group variability in drug sensitivity of hub CRGs and CIR-score. The combination of immunotherapy, targeted therapy, and chemotherapy exhibited a better tumor suppression effect.ConclusionCIR-score, as a Cuproptosis-related TIME-specific prognostic signature based on PAAD single cells, not only predicts the prognosis and immune landscape of PAAD patients but also provides a new strategy for individualized immunotherapy-based combination therapy.

【 授权许可】

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Copyright © 2023 Sun, Yao, Man, Gao, He and Fan