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Identification of an antigen-presenting cells/T/NK cells-related gene signature to predict prognosis and CTSL to predict immunotherapeutic response for lung adenocarcinoma: an integrated analysis of bulk and single-cell RNA sequencing

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Abstract

Background

Antigen-presenting cells (APC)/T/NK cells are key immune cells that play crucial roles in fighting against malignancies including lung adenocarcinoma (LUAD). In this study, we aimed to identify an APC/T/NK cells-related gene signature (ATNKGS) and potential immune cell-related genes (IRGs) to realize risk stratification, prognosis, and immunotherapeutic response prediction for LUAD patients.

Methods

Based on the univariate Cox regression and the LASSO Cox regression results of 196 APC/T/NK cells-related genes collected from three pathways in the KEGG database, we determined the final genes and established the ATNKGS-related risk model. The single-cell RNA sequencing data were applied for key IRGs identification and investigate their value in immunotherapeutic response prediction. Several GEO datasets and an external immunotherapy cohort from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were applied for validation.

Results

In this study, nine independent public datasets including 1108 patients were enrolled. An ATNKGS containing 16 genes for predicting overall survival of LUAD patients was constructed with robust prognostic capability. The ATNKGS high risk group was related to significantly worse OS outcomes than those in the low-risk group, which were verified in TCGA and four GEO datatsets. A nomogram combining the ATNKGS risk score with clinical TNM stage achieved the optimal prediction performance. The single-cell RNA sequencing analysis revealed CTSL as an IRG of macrophage and monocyte. Moreover, though CTSL was an indicator for poor prognosis of LUAD patients, CTSL high expression group was associated with higher ESTIMATEScore, immune checkpoints expression, and lower TIDE score. Several immunotherapeutic cohorts have confirmed the response-predicting significance of CTSL in patients receiving immune checkpoint inhibitor (ICI) treatment.

Conclusions

Our study provided an insight into the significant role of APC/T/NK cells-related genes in survival risk stratification and CTSL in response prediction of immunotherapy in patients with LUAD.

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Data availability

The datasets used in the current study are available from the corresponding author upon reasonable request.

Abbreviations

APC:

Antigen-presenting cells

ATNKGS:

APC/T/NK cells-related gene signature

AUC:

Area under the curve

CTLA4:

Cytotoxic T-lymphocyte-associated antigen 4

CI:

Confidence interval

CR:

Complete response

ESTIMATE:

Estimation of stromal and immune cells in malignant tumors using expression data

FFPE:

Formalin-fixed paraffin-embedded

GOBP:

Gene ontology biological process

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IRG:

Immune-related gene

KEGG:

Kyoko encyclopedia of genes and genomes

LASSO:

Least absolute shrinkage and selection operator

LUAD:

Lung adenocarcinoma

MATH:

Mutant-allele tumor heterogeneity

MPS:

Mononuclear phagocyte system

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death-ligand 1

PFS:

Progression-free survival

PR:

Partial response

ROC:

Receiver operating characteristic

scRNA:

Single-cell RNA

SD:

Stable disease

TIDE:

Tumor immune dysfunction and exclusion

TME:

Tumor microenvironment

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Acknowledgements

We thank the data donors and research groups of TCGA-LUAD, GSE11969, GSE31210, GSE37745, GSE50081, GSE126044, GSE135222, and GSE117570. We thank the public TCGA, GEO, and KEGG databases, as well as UCSC Xena website, thank the patients in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College who provided samples in this study. We also would like to thank Wu et al.’s article (https://doi.org/10.1038/s41388-021-01853-y) and He et al.’s article (https://doi.org/10.1093/bib/bbac291) as Figures 2 and 3 in this study referred to the typesetting format of their articles.

Funding

This work was funded by China National Major Project for New Drug Innovation (2017ZX09304015) and Major Project of Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOMP2022006).

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Author notes

  1. Liling Huang, Ning Lou and Tongji Xie have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China

    Liling Huang, Tongji Xie, Le Tang & Yuankai Shi

  2. Department of Clinical Laboratory, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China

    Ning Lou

  3. Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China

    Xiaohong Han

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Contributions

YKS and XHH contributed to supervision, conceptualization, funding acquisition, project administration, and writing—review and editing. LLH helped in data curation, visualization, writing—original draft, and writing—review and editing. NL helped in data curation, visualization, and writing—review and editing; TJX contributed to visualization and writing—review and editing. Le Tang contributed to writing—review and editing. All authors contributed to manuscript revision and final approval.

Corresponding authors

Correspondence to Xiaohong Han or Yuankai Shi.

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Ethical statement

The study was conducted according to the guidelines of the Declaration of Helsinki, was approved by the institutional ethical committee of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (19–019/1804), and informed consent was obtained from all patients.

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Huang, L., Lou, N., Xie, T. et al. Identification of an antigen-presenting cells/T/NK cells-related gene signature to predict prognosis and CTSL to predict immunotherapeutic response for lung adenocarcinoma: an integrated analysis of bulk and single-cell RNA sequencing. Cancer Immunol Immunother 72, 3259–3277 (2023). https://doi.org/10.1007/s00262-023-03485-5

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