Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status - PubMed (original) (raw)

. 2016 Oct;70(4):623-632.

doi: 10.1016/j.eururo.2015.11.029. Epub 2015 Dec 23.

Sophie Gad 2, Muhammad Zaeem Noman 1, Gwenael Le Teuff 3, Sophie Couve 2, Bassam Janji 4, Solenne Florence Kammerer 5, Nathalie Rioux-Leclerc 5, Meriem Hasmim 1, Sophie Ferlicot 6, Véronique Baud 7, Arnaud Mejean 8, David Robert Mole 9, Stéphane Richard 2, Alexander M M Eggermont 10, Laurence Albiges 11, Fathia Mami-Chouaib 1, Bernard Escudier 11, Salem Chouaib 12

Affiliations

Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status

Yosra Messai et al. Eur Urol. 2016 Oct.

Abstract

Background: Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene.

Objective: To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression.

Design, setting, and participants: A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation.

Outcome measurements and statistical analysis: Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions.

Results and limitations: We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells.

Conclusions: Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy.

Patient summary: We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We demonstrated that von Hippel-Lindau mutation status significantly correlated with programmed death-ligand 1 expression in clear cell renal cell carcinomas.

Keywords: HIF-2α; PD-L1; VHL mutations; ccRCC.

Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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