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.
Highlights
Bladder cancer is the 11th most common cancer and the 9th most common cause of cancer mortality in the UK
To define whether tumor cells express PD-L2 protein, we employed the use of Tissue microarrays (TMAs) comprising a range of bladder cancer stages and grades (Table 1)
The use of PD-1 and PD-L1 inhibitors is commonplace in many clinical settings, including the treatment of muscle-invasive bladder cancer (MIBC), and trials in NMIBC are ongoing [19]
Summary
Bladder cancer is the 11th most common cancer and the 9th most common cause of cancer mortality in the UK. The majority of cases derive from the urothelium (urothelial bladder cancer - UBC), a specialised epithelial layer lining the urinary tract. The majority of UBC patients present with nonmuscle-invasive (NMIBC) disease, whereas the presence or progression to muscle-invasive (MIBC) disease is associated with significantly increased cancer mortality [1]. Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. UBC is an ideal setting for ICB as evidenced by landmark trials and FDA licencing of anti-PD-1 and anti-PD-L1 antibodies [2]. Whilst 15%–29% of patients exhibit an objective response to checkpoint inhibitors, the majority of patients fail to respond [3]. Many questions remain to be answered in order to permit informed clinical decisionmaking, alongside continued therapeutic development and further advancement of the field
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