A functional role for glycosylated B7-H5/VISTA immune checkpoint protein in metastatic clear cell renal cell carcinoma.

Increased expression of the B7 family of immune checkpoint proteins hinders tumor elimination by the immune system. Expression levels of the B7-H5 protein were found to be upregulated in clear cell renal cell carcinomas (ccRCC). We here report the molecular, functional, and clinical characterization of B7-H5 from renal cancer cells and metastatic ccRCC tumors. B7-H5 was highly glycosylated and mainly expressed in the cell membrane. Mutagenic studies on B7-H5 identified the residues targeted by N-glycosylation and revealed an impact of B7-H5 glycosylation on protein expression levels and localization. B7-H5 knockdown decreased the cell proliferation and viability of renal cancer cells. We analyzed B7-H5 expression on tumor cells and tumor-infiltrated leukocytes (TILs) in samples from metastatic ccRCC patients and found that B7-H5 expression on TILs correlated with syncronous metastases and poor outcomes. These results provide insights into the molecular properties and clinical impact of B7-H5 and support B7-H5 as a new immunotherapeutic target in metastatic ccRCC.