The immune checkpoint protein PD-L1 is aberrantly expressed in several tumor types including clear cell renal cell carcinoma (ccRCC). The mechanism of the upregulation of PD-L1 in ccRCC is still unknown.
As the loss of function of the Von Hippel-Lindau protein (pVHL) with the resulting activation of HIF target genes is a hallmark of ccRCC, we asked whether PD-L1 expression might be regulated by HIF. In our study we demonstrate that ccRCC cell lines with impaired function of pVHL to degrade HIFα express elevated levels of PD-L1. In vitro analysis provided evidence that both reconstitution of pVHL and silencing of HIF2α, but not of HIF1α, lead to reduced PD-L1 expression. The strong correlation of expression between the HIF2α-specific HIF target Glut1 and PD-L1 confirmed this finding in ccRCC cell lines and tissue. Soluble PD-L1 levels remained constant in the sera of ccRCC patients regardless of the PD-L1 expression status in their tumors. In conclusion, our data suggest PD-L1 as HIF2α target, which is upregulated in pVHL deficient ccRCC. The combination of PD-L1 targeting drugs with HIF inhibiting agents may be an additional option for the treatment of ccRCC. This article is protected by copyright. All rights reserved.
International journal of cancer. 2016 Mar 04 [Epub ahead of print]
Melanie Ruf, Holger Moch, Peter Schraml
Institute of Surgical Pathology, University Hospital Zurich, Switzerland., Institute of Surgical Pathology, University Hospital Zurich, Switzerland., Institute of Surgical Pathology, University Hospital Zurich, Switzerland.