Circular RNA hsa_circ_0000190 Facilitates the Tumorigenesis and Immune Evasion by Upregulating the Expression of Soluble PD-L1 in Non-Small-Cell Lung Cancer.

Ping-Hsing Tsai,Yuh-Min Chen,Yueh Chien,Yi-Ping Yang,Yung-Hung Luo,Shih-Hwa Chiou,Tzu-Wei Lin,Mong-Lien Wang,Afeez Adekunle Ishola,Aliaksandr A Yarmishyn,Chian-Shiu Chien

doi:10.3390/ijms23010064

Abstract

Lung cancer is the leading cause of death from cancer in Taiwan and throughout the world. Immunotherapy has revealed promising and significant efficacy in NSCLC, through immune checkpoint inhibition by blocking programmed cell death protein (PD)-1/PD-1 ligand (PD-L1) signaling pathway to restore patients’ T-cell immunity. One novel type of long, non-coding RNAs, circular RNAs (circRNAs), are endogenous, stable, and widely expressed in tissues, saliva, blood, urine, and exosomes. Our previous results revealed that the plasma level of hsa_circ_0000190 can be monitored by liquid-biopsy-based droplet digital PCR and may serve as a valuable blood-based biomarker to monitor the disease progression and the efficacy of immunotherapy. In this study, hsa_circ_0000190 was shown to increase the PD-L1 mRNA-mediated soluble PD-L1 (sPD-L1) expression, consequently interfering with the efficacy of anti-PD-L1 antibody and T-cell activation, which may result in immunotherapy resistance and poor outcome. Our results unraveled that hsa_circ_0000190 facilitated the tumorigenesis and immune evasion of NSCLC by upregulating sPD-L1 expression, potentially developing a different aspect in elucidating the molecular immunopathogenesis of NSCLC. Hsa_circ_0000190 upregulation can be an effective indicator for the progression of NSCLC, and hsa_circ_0000190 downregulation may possess a potential therapeutic value for the treatment of NSCLC in combination with immunotherapy.

Highlights

Lung cancer (LC) is the leading cause of death worldwide, and more than 85% of LC cases belong to non-small-cell lung carcinoma (NSCLC) [1]
To analyze the biological role of C190overexpression group (C190) in NSCLC, overexpression vectors targeting C190 were delivered into NSCLC cell lines
The data show that A549 with overexpression of C190 demonstrated significantly increased cell migration and invasion, compared with the negative control (NC) cells (* p < 0.05)

Summary

Introduction

Lung cancer (LC) is the leading cause of death worldwide, and more than 85% of LC cases belong to non-small-cell lung carcinoma (NSCLC) [1]. The emergence of targeted therapies and immunotherapies has led to remarkable improvement in the treatment efficacy for NSCLC, but the survival rate for advanced NSCLC still remains dismal [1,2,3,4,5,6,7,8]. Despite the significant advancement in the medical treatment of LC, fewer than 10% of advanced NSCLC patients survive for more than five years. The development of superior diagnostic and therapeutic approaches is critical for a better understanding of the molecular pathogenesis of LC. Such advancements can contribute to the discovery of novel biomarkers for cancer detection and molecular treatment targets for LC, as well as more personalized treatment of LC patients

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Discussion

Conclusion