PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma
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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.
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The HIF-α dependency of PD-L1 is tumor-type dependent: PD-L1 expression is primarily HIF-1α driven in HIF-1α-dominant cancers (CT26 colon carcinoma and 4T1 breast carcinoma models) and HIF-2α-driven in HIF-2α-dominant cancers (ccRCC).
“As seen for the other cancer axes, the HIF-α dependency of PD-L1 is tumor-type dependent, with PD-L1 expression primarily HIF-1α driven in HIF-1α-dominant cancers (such as CT26 colon carcinoma and 4T1 breast carcinoma models) and HIF-2α-driven in HIF-2α-dominant cancers (ccRCC) [81, 83].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [83]
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- Authors
- Ruf, M., Moch, H., & Schraml, P.
- Affiliations
- University Hospital Zurich (CH)
- Corresponding author
- Ruf, Melanie
- Schraml, Peter
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2016-03-25
- Volume
- 139
- Issue
- 2
- Pages
- 396-403
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2291094902
- Cited by
- 179
- References
- 38
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 13 · 2023: 18 · 2022: 20 · 2021: 28 · 2020: 27 · 2019: 24 · 2018: 24 · 2017: 11 · 2016: 4
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Swiss National Cancer Foundation (3238BO-10314)
- Zurich Cancer League (to H.M.)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- PD-L1, clear cell renal cell carcinoma, hypoxia-inducible factor, HIF-2α, HIF-1α, von Hippel-Lindau protein, VHL deficiency, HIF target genes, GLUT1, soluble PD-L1, HIF inhibitors, immune checkpoint inhibitors
- MeSH terms
- Carcinoma, Renal Cell, Humans, Immunohistochemistry, Kidney Neoplasms, Mutation, Gene Expression, Gene Expression Regulation, Neoplastic, Case-Control Studies, Gene Silencing, Cell Line, Tumor, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, B7-H1 Antigen
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