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Abstract
The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.
Original language | English |
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Article number | 626748 |
Number of pages | 7 |
Journal | Frontiers in Oncology |
Volume | 11 |
DOIs | |
Publication status | Published - 25 Feb 2021 |
Bibliographical note
Funding Information:The BCPP study was funded by Cancer Research UK (C1343/ A5738), the University of Birmingham and the Birmingham and The Black Country and West Midlands North and South Comprehensive Local Research Networks. BCPP is under the sponsorship of the University of Birmingham.
Funding Information:
The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We are thankful to Prof. Lars Dyrskjøt (Aarhus University) for kindly providing the gene expression count data for Hedegaard et al. cohort (17). We gratefully acknowledge the contribution made by the University of Birmingham’s Human Biomaterials Resource Centre supported through Birmingham Science City— Experimental Medicine Network of Excellence project. We are grateful to the urologists and urology nurses of the West Midlands for their significant contributions to the recruitment and follow-up of BCPP participants.
Publisher Copyright:
© Copyright © 2021 Dowell, Munford, Goel, Gordon, James, Cheng, Zeegers, Ward and Bryan.
Keywords
- PD-L1 (B7-H1 CD274)
- PD-L2: programmed cell death ligand 2
- bladder cancer
- immune checkpoint inhibitors
- normal urothelium
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Dive into the research topics of 'PD-L2 is constitutively expressed in normal and malignant urothelium'. Together they form a unique fingerprint.Projects
- 2 Finished
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Bladder Cancer Prognosis Programme
Bryan, R. (Principal Investigator)
1/05/10 → 31/07/13
Project: Other Government Departments
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Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer
Cheng, K. (Principal Investigator), Zeegers, M. (Co-Investigator), James, N. (Co-Investigator), Billingham, L. (Co-Investigator), Hussain, S. (Co-Investigator) & Murray, P. (Co-Investigator)
Cancer Research UK, NIHR, DUDLEY GROUP OF HOSPITALS
1/05/05 → 31/08/11
Project: Research