High PVR protein expression marks clear cell renal cell carcinoma with metastatic spread.

Background: The poliovirus receptor (PVR) is an emerging therapeutic target currently under clinical investigation in combination with checkpoint inhibitors. Although it is broadly expressed across many malignancies, its prognostic and predictive value in renal and bladder cancers remains underexplored. Methods: Quantitative immunohistochemical analysis of PVR expression was performed in tumor tissue from patients with bladder cancer or renal cell carcinoma, including clear cell and papillary subtypes. Matched serum samples were analyzed using a custom enzyme-linked immunosorbent assay for total circulating PVR. To distinguish isoforms, we generated an antibody specific to the secreted isoform and developed an isoform-selective assay. Results: Serum PVR levels were elevated in both bladder and renal cancer patients but did not correlate with tumor tissue expression, whether total or isoform-specific. In bladder cancer, tissue levels correlated with tumor grade and lymphovascular invasion. In renal cancer, expression was subtype-dependent, with only a subset of clear cell carcinoma samples showing tissue positivity. Importantly, reduced overall survival in clear cell carcinoma was linked to PVR expression, and rare cases with high levels consistently progressed to metastatic disease. Conclusion: In renal tumors, a preliminary subtype-specific pattern emerged: PVR expression was generally low in clear cell carcinoma but enriched in papillary carcinoma. Notably, in the expanded clear cell cohort all cases with high expression were associated with metastatic progression. These findings highlight PVR in tumor biopsies as a potential prognostic marker in clear cell carcinoma and support its further investigation as a biomarker and therapeutic target in renal cancers.