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.
Messai Yosra,Gad Sophie,Noman Muhammad Zaeem,Le Teuff Gwenael,Couve Sophie,Janji Bassam,Kammerer Solenne Florence,Rioux-Leclerc Nathalie,Hasmim Meriem,Ferlicot Sophie,Baud Véronique,Mejean Arnaud,Mole David Robert,Richard Stéphane,Eggermont Alexander M M,Albiges Laurence,Mami-Chouaib Fathia,Escudier Bernard,Chouaib Salem
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.
PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma.
Ruf Melanie,Moch Holger,Schraml Peter
International journal of cancer
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.
Hypoxia-inducible factor-1α: a promising therapeutic target for autoimmune diseases.
Guan Shi-Yang,Leng Rui-Xue,Tao Jin-Hui,Li Xiang-Pei,Ye Dong-Qing,Olsen Nancy,Zheng Song Guo,Pan Hai-Feng
Expert opinion on therapeutic targets
INTRODUCTION:Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases. Areas covered: Considering that the types of autoimmune diseases are complicated and various, this review aims to cover the typical kinds of autoimmune diseases, discuss the molecular mechanisms, biological functions and expression of HIF-1α in these diseases, and further explore its therapeutic potential. Expert opinion: Inflammation and hypoxia are interdependent. HIF-1α as a key regulator of hypoxia, exerts a crucial role in the balance between Th17 and Treg, and involves in the inflammation and pathologic activities of autoimmune diseases. Although there are many challenges remaining to be overcome, targeting HIF-1α could be a promising strategy for autoimmune diseases therapies.