Aims The advent of immune checkpoint inhibitor therapy has proven beneficial in a subset of high-grade urothelial carcinomas (HGUC) of the bladder. Although treatment selection is currently largely determined by programmed death-ligand 1 (PD-L1) status, multiple factors in the immune system may modulate the host immune response to HGUC and immunotherapy. In this pilot study, we used a transcriptomic approach to identify the immune milieu associated with PD-L1 expression to enhance our understanding of the HGUC immune evasion network.
Methods The immune transcriptome of 40 HGUC cystectomy cases was profiled using the NanoString nCounter Human V.1.1 PanCancer Panel. All cases were assessed for associated PD-L1 status (SP263) using whole tissue sections. PD-L1 status was determined as high or low using 25% tumour and/or immune cell staining.
Results The most significantly differentially expressed gene was PD-L1 messenger RNA (CD274), which strongly correlated with protein expression (r=0.720, p<0.001). The sensitivity, specificity, positive and negative predictive values of CD274 for PD-L1 expression were 85%, 96%, 92% and 93%, respectively. The PD-L1 associated gene signature also included complement components C1QA and CD46 and NOD2 (innate immune system), proinflammatory cytokines CXCL14, CXCL16, CCL3, CCL3L1 and OSM along with the immune response mediator SMAD3, among others. Pathway analysis determined enrichment of these genes in interleukin-10 production, lymphocyte chemotaxis and aberrant IFNγ, NF-κB and ERK signalling networks.
Conclusions We report key genes and pathways in the immune transcriptome and their association with PD-L1 status, which may be involved in immune evasion of HGUC and warrants further investigation.
- urinary bladder
- pathology, molecular
- urologic neoplasms
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Handling editor Runjan Chetty.
Contributors MRD designed the study. AH, BX and MRD gathered the immunohistochemistry data. JB and JB performed the gene expression profiling. EO-M, AH, SKL, DV, BX and MRD reviewed and interpreted the data. EO-M performed the RNA extraction and statistical analysis. EO-M, AH, SKL, DV, BX, JB, JB and MRD contributed to drafting and review of the manuscript, and to approval of the final version.
Funding The SP263 antibody was purchased using a Sunnybrook Health Sciences Centre departmental Educational Grant courtesy of AstraZeneca.
Competing interests MRD has been an advisory board member for AstraZeneca and Hoffmann-La Roche and has received speaker’s honoraria from AstraZeneca.
Patient consent for publication Not required.
Ethics approval This study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre (REB 187–2016)
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request from corresponding author.