Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients

Authors

  • Ingrid M.E. Desar,

    1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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    • I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.

  • J. (Hans) F.M. Jacobs,

    1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    3. Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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    • I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.

  • Christina A. Hulsbergen-vandeKaa,

    1. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Wim J.G. Oyen,

    1. Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Peter F.A. Mulders,

    1. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Winette T.A. van der Graaf,

    1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Gosse J. Adema,

    1. Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Carla M.L. van Herpen,

    1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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    • I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.

  • I. (Jolanda) J.M. de Vries

    Corresponding author
    1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    3. Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    • NCMLS, TIL 278, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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    • I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.

    • Tel.: 0031 24 3617600, Fax: 31-24-3540339


Abstract

Tyrosine kinase inhibitors (TKIs) as sorafenib are known to reduce the number of immunosuppressive regulatory T cells (Tregs) in the peripheral blood and thereby shifting the immune balance to a more stimulating setting. The effect of sorafenib on intratumoural Tregs is unclear but important for future combinations of TKIs and immunotherapy. We, therefore, evaluated the accumulation of regulatory T cells (Tregs, defined as, CD4+FoxP3+CD25highCD127low-cells) in blood, ascites, metastases and primary tumours of patients with renal cell carcinoma (RCC), and we explored the effect of neoadjuvant treatment with sorafenib 400 mg bid on intratumoural Tregs in 11 patients with RCC in comparison to 15 nontreated RCC patients. We found that immunosuppressive Tregs specifically accumulate in primary tumour, metastases and ascites of RCC-patients. Tumour infiltrating Tregs were functional. Neoadjuvant sorafenib treatment significantly reduced the percentage of tumour-infiltrating Tregs (mean 17.3% vs. 28.1%, p = 0.046). Diminished Treg accumulation at the tumour site adds to explain the clinical effectiveness of sorafenib treatment. This observation may have important implications for the use of sorafenib in combination with immunotherapy in patients with RCC, since the depletion of Tregs has been associated with enhanced responses on vaccine mediated immunotherapy.

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