PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

Area of Science:

• Immunology
• Oncology
• Urothelial Carcinogenesis

Background:

• Immune checkpoint inhibitors targeting PD-1/PD-L1 are standard treatments for muscle-invasive bladder cancer (MIBC).
• Limited data exists on PD-L2, an alternative ligand for PD-1, in urothelial bladder cancer (UBC).

Purpose of the Study:

• To characterize PD-L2 expression in UBC and compare it with PD-L1.
• To investigate the role of PD-L2 in normal urothelium and its potential shedding in MIBC.

Main Methods:

• Immunohistochemistry to assess PD-L2 protein expression in UBC.
• RNA-sequencing analysis of PDCD1LG2 (PD-L2) and CD274 (PD-L1) expression in 575 UBC patients.
• Investigation of PD-L2 expression in normal urothelium.

Main Results:

• Widespread PD-L2 expression was observed in UBC via immunohistochemistry, with reduced levels in MIBC.
• RNA-seq data confirmed widespread PD-L2 expression, correlated with PD-L1, and showed increased expression in advanced disease.
• Constitutive PD-L2 expression in normal urothelium was identified, with a proposed mechanism for its cell surface cleavage in MIBC.

Conclusions:

• PD-L2 is abundant in UBC and constitutively present in normal urothelium.
• Expression patterns of PD-L2 vary between normal, early, and advanced bladder cancer.
• These findings have implications for developing novel immune checkpoint therapies and understanding bladder immune function.