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[Cuproptosis-related immune gene signature predicts clinical benefits from anti-PD-1/PD-L1 therapy in non-small-cell lung cancer

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Abstract

Non-small-cell lung cancer (NSCLC) remains the major cause of cancer-related death. Immune checkpoint inhibition has become the cornerstone treatment for NSCLC. Cuproptosis is a newly identified form of cell death relying on mitochondrial respiration that might play a role in shaping tumor immune microenvironment (TIME). The clinical significance of cuproptosis-related genes (CRGs) remains unclear and warrant investigation. The current study extracted RNA sequencing profiles and corresponding clinical information from six aggregated datasets from the Gene Expression Omnibus (GEO) repository as the training set, and from The Cancer Genome Atlas (TCGA) database as the testing set. Cuproptosis-related immune genes (CRIMGs) were obtained through coexpression analysis, univariate Cox regression analysis, and LASSO analysis for overall survival (OS) association analysis. Consensus clustering was employed to divide the subjects into clusters. Stepwise multivariate Cox regression was used to establish the prognostic CRIMG_score from the CRIMGs. A 17-gene prediction signature was established that informed patients’ OS both in the training and testing datasets (p < 0.001). The predictive value of the signature in terms of immunotherapeutic responses was assessed in two publicly available NSCLC immunotherapy datasets (POPLAR and OAK studies) and an internal dataset from Sun Yat-sen University Cancer Center (ORIENT-11 study). Patients in the high-risk group displayed worse survival, a characteristic suppressive tumor immune microenvironment, and low immunotherapeutic benefits compared to those in the low-risk group. Collectively, the CRIMG_score established herein could serve as a promising indicator of prognosis and immunotherapeutic response in patients with NSCLC.

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Data availability

RNA-sequence were from GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc = GSE101929/GSE29013/GSE30219/GSE31210/GSE37745/GSE50081). TPM-normalized counts from RNAseq data and Clinical data in POPLAR and OAK cohorts are available under restricted access in the European Genome-Phenome Archive under accession numbers EGAS00001004343 and EGAS00001005013, respectively (https://ega-archive.org/).

The remaining data analyzed during this study are included within the published article and its supplementary information files. Data for ORIENT-11 from Sun Yat-sen University Cancer Center was available on reasonable request by the corresponding authors.

Abbreviations

CRGs :

Cuproptosis-related genes

CRIMG :

Cuprotosis-related immune genes

TIME :

Tumor immune microenvironment

PCA :

Principal component analysis

OS :

Overall survival

NSCLC :

Non-small-cell lung cancer

TCA :

Tricarboxylic acid

ICI :

Immune checkpoint inhibitor

ICD :

Inflammatory cell deaths

DAMP :

Damage-associated molecular patterns

GEO :

Gene Expression Omnibus

TCGA :

The Cancer Genome Atlas

CDF :

Cumulative distribution function

ssGSEA :

Single-sample gene set enrichment analysis

GSEA :

Gene set enrichment analyses

FDR :

False discovery rate

KEGG :

Kyoto Encyclopedia of Genes and Genomes

GO :

Gene Ontology

BP :

Biological process

MF :

Molecular function

CC :

Cellular component

ROC :

Receiver operating characteristic curve

LDH :

Lactate dehydrogenase

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Funding

This study was supported by National Natural Science Foundation of China (grants numbers 81972898, 8217102281, 82072558); the Natural Science Foundation of Guangdong Province (2019A1515011090); and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22ykqb15).

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Author notes

  1. Linfeng Luo, Anlin Li, and Sha Fu contributed equally.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangzhou, China

    Linfeng Luo, Anlin Li, Wei Du, Li-Na He, Xuanye Zhang, Yixing Wang, Yixin Zhou, Yang Yunpeng, Zhang Li & Shaodong Hong

  2. Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Linfeng Luo, Anlin Li, Wei Du, Li-Na He, Xuanye Zhang, Yixing Wang, Yixin Zhou, Yang Yunpeng, Zhang Li & Shaodong Hong

  3. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, China

    Linfeng Luo, Anlin Li, Wei Du, Li-Na He, Xuanye Zhang, Yixing Wang, Yang Yunpeng, Zhang Li & Shaodong Hong

  4. Department of Cellular & Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Sha Fu

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-Sen University, Guangzhou, 510120, China

    Sha Fu

  6. Department of VIP Region, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Yixin Zhou

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Contributions

L. L. F, F. S., and S. D. H. designed the study. Z. L. and Y. Y. P. provided the in-house data. L. L. F. and A. L. L. draft the manuscript and designed the figures. W. D., F. S., and L. N. H. revised the manuscript. X. Y. Z., Y. X. W., and Y. X. Z. collected the clinical information of immunotherapy cohorts. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Shaodong Hong.

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Study protocol for the ORIENT-11 clinical trial was approved by the respective institutional review boards and ethics committees and all participants provided written informed consent. Ethics approval and patient informed consents for TCGA, GEO, and EGA were waived due to their public availability.

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The authors declare no competing interests.

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Yang Yunpeng, Zhang Li, and Shaodong Hong were co-communicators.

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Luo, L., Li, A., Fu, S. et al. [Cuproptosis-related immune gene signature predicts clinical benefits from anti-PD-1/PD-L1 therapy in non-small-cell lung cancer. Immunol Res 71, 213–228 (2023). https://doi.org/10.1007/s12026-022-09335-3

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