Screening and validation of plasma cell-derived, purinergic, and calcium signalling-related genetic signature to predict prognosis and PD-L1/PD-1 blockade responses in lung adenocarcinoma

Junfeng Huang; Xingyu Fan; Bingqi Hu; Liwen Chen

doi:10.1007/s00432-023-05153-8

Screening and validation of plasma cell-derived, purinergic, and calcium signalling-related genetic signature to predict prognosis and PD-L1/PD-1 blockade responses in lung adenocarcinoma

J Cancer Res Clin Oncol. 2023 Nov;149(14):12931-12945. doi: 10.1007/s00432-023-05153-8. Epub 2023 Jul 19.

Authors

Junfeng Huang^#^{1

2}, Xingyu Fan^#³, Bingqi Hu^{1

2}, Liwen Chen^{4

5}

Affiliations

¹ Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
² Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
³ Medicine Centre, Erasmus University, Rotterdam, The Netherlands.
⁴ Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. chenliwen@ahmu.edu.cn.
⁵ Department of Blood Transfusion, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. chenliwen@ahmu.edu.cn.

^# Contributed equally.

PMID: 37468608
DOI: 10.1007/s00432-023-05153-8

Abstract

Background: This study aims at screening and validation of prospective genetic signature for lung adenocarcinoma (LUAD) prognosis and treatment.

Methods: The immune-related genes (IRGs) were obtained from The Cancer Genome Atlas (TCGA) dataset where a total of 535 LUAD and 59 control samples were included. A risk model was then developed for the risk stratification of LUAD patients. The immune cell infiltration, clinical outcomes, and the therapeutic efficacy of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) blockade were compared between high and low-risk groups. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to explore the biological processes and signalling pathways associated with the IRGs. Finally, IRGs mRNA levels were assayed by reverse transcription quantitative real-time PCR (RT-qPCR) in LUAD and relevant cell lines.

Results: Two IRGs, P2RX1 (purinergic receptor P2X 1) and PCP4 (Purkinje cell protein 4), were screened from a module that possesses the highest correlation with plasma cells. RT-qPCR verified the expression of the two IRGs in plasmacytoma cell RPMI 8226 but not in LUAD cells. A higher risk score is associated with a lower infiltration of immune cells. Kaplan-Meier and nomogram analysis showed that the high-risk group has a lower survival rate than the low-risk cohort. Furthermore, the high-risk group had a worse response rate to PD-L1/PD-1 blockade. GSVA and GSEA-GO results indicated that a lower risk score is linked to signalling pathways and biological functions promoting immune response and inflammation. In contrast, a higher risk score is associated with signalling cascades promoting tumour growth.

Conclusion: The immune-related prognostic model based on P2RX1 and PCP4 is conducive to predicting the therapeutic response of PD-L1/PD-1 blockade and clinical outcomes of LUAD.

Keywords: Immunotherapy; Lung adenocarcinoma; P2RX1; PCP4; Plasma cell.

Abstract

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