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Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

Oncogene volume 30, pages 2622–2632 (2011)Cite this article

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Abstract

The tumor suppressor gene von Hippel–Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-α results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1α and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNγ secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNα, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNα resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL.

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Acknowledgements

This work was supported by grants from INSERM, INCa, la Fondation pour la Recherche Medicale (FRM) and la Ligue Nationale contre le Cancer. AP had a grant from FRM. We thank Dr Nadege Bercovici for helpful discussion and reading of manuscript.

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Authors and Affiliations

  1. Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, France

    A Perier, G Fregni & A Caignard

  2. INSERM U753, Institut Gustave Roussy, Villejuif, France

    S Wittnebel

  3. Laboratoire de Génétique Oncologique EPHE, INSERM U753, Institut Gustave Roussy, Villejuif, France

    S Gad

  4. INSERM U892, Nantes, France

    M Allard & N Gervois

  5. Departement d’oncologie Médicale, Institut Gustave Roussy, Villejuif, France

    B Escudier

  6. Institut National de la Sante et de la Recherche Médicale, UMR 542, Université de Paris-Sud, Hôpital Paul Brousse, Villejuif, France

    B Azzarone

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  1. A Perier
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Correspondence to A Caignard.

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Perier, A., Fregni, G., Wittnebel, S. et al. Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma. Oncogene 30, 2622–2632 (2011). https://doi.org/10.1038/onc.2010.638

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