Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study

Abstract

Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

“…A recent study has revealed that both ADAM10 and ADAM17 can cleave PD-L1 from the surface of malignant cells (such as 786-0 renal cell carcinoma that express both the checkpoint ligand and the two proteases) but also extracellular vesicles. ADAM proteases are considered cleavers of PD-L1 from the surface of cancer cells (e.g., bladder tumor cells) and possibly also from immune cells [ 94 ]. ADAMs, ADAM10 in particular, are known to be present in small extracellular vesicles and responsible for ectodomain shedding [ 95 , 96 ].…”

Programmed Cell Death-Ligand-1 expression in Bladder Schistosomal Squamous Cell Carcinoma – There’s room for Immune Checkpoint Blockage?

“…(2021) showed a positive correlation between serum MMP-7 and sPD-L1 in patients with BUC, while Pichler et al. (2021) demonstrated an inverse correlation between mPD-L1 and ADAM17 bladder tissue expression ( 77 , 82 ).…”

“…In this regard, further studies are needed since the expression of PD-L1 can be dynamic, as seen in studies that reported divergent expressions or weak correlations between mPD-L1 and sPD-L1 ( 77 , 78 ). It was shown that mPD-L1 expression correlated with the expression of metalloproteinases in both tissue and serum ( 77 , 82 ). Krafft et al.…”

Nephron-Sparing Approaches in Upper Tract Urothelial Carcinoma: Current and Future Strategies

“…Studies related to factors that can predict the effectiveness of BCG treatment in bladder cancer have been conducted. Pichler et al [ 51 ] performed immunohistochemical staining with PD-L1, GATA-3, IL10/IL-10 receptor, and a disintegrin and metalloproteinase (ADAM) protease from radical cystectomy specimens after BCG failure. They reported that the expression of ADAM17, which has been reported to release membrane-bound PD-L1, is high in tumor regions.…”