VHL promotes immune response against renal cell carcinoma via NF-κB–dependent regulation of VCAM-1

Vascular cell adhesion molecule1 ( VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesionand extravasation. However, its expression in renal carcinomas inversely correlates with tumor malignancy. Our experiments in clear cell renal cell carcinoma(ccRCC) cell lines demonstrated that von HippelLindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain–containing proteins) inactivation decreased VCAM-1levels through a transcriptional mechanism that was independent of the hypoxia-inducible factorand dependent on the nuclear factor κB signaling pathway. Conversely, VHL expression leads to high VCAM-1levels in ccRCC, which in turn leads to better outcomes, possibly by favoring antitumor immunity through VCAM-1interaction with the α4β1 integrin expressed in immune cells. Remarkably, in ccRCC human samples with VHL nonmissense mutations, we observed a negative correlation between VCAM-1levels and ccRCC stage, microvascular invasion, and symptom presentation, pointing out the clinical value of VCAM-1levels as a marker of ccRCC progression.