Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients
Ingrid M.E. Desar
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorJ. (Hans) F.M. Jacobs
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorChristina A. Hulsbergen-vandeKaa
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWim J.G. Oyen
Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorPeter F.A. Mulders
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWinette T.A. van der Graaf
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorGosse J. Adema
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorCarla M.L. van Herpen
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorCorresponding Author
I. (Jolanda) J.M. de Vries
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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
NCMLS, TIL 278, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorIngrid M.E. Desar
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorJ. (Hans) F.M. Jacobs
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorChristina A. Hulsbergen-vandeKaa
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWim J.G. Oyen
Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorPeter F.A. Mulders
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWinette T.A. van der Graaf
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorGosse J. Adema
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorCarla M.L. van Herpen
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
I.M.E.D., J.F.M.J., V.M.L. van H. and I.J.M. de V contributed equally.
Search for more papers by this authorCorresponding Author
I. (Jolanda) J.M. de Vries
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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
NCMLS, TIL 278, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorTel.: 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.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
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| IJC_25674_sm_suppfig-S1.tif82.4 KB | Supporting Figure S1 |
| IJC_25674_sm_suppfig-S2.tif92.9 KB | Supporting Figure S2 |
| IJC_25674_sm_suppfig-S3.tif76.8 KB | Supporting Figure S3 |
| IJC_25674_sm_suppTable.doc48.5 KB | Supporting Table |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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