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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5610-5620. Prepublished online as a Blood First Edition Paper on February 29, 2008; DOI 10.1182/blood-2007-02-075945. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-075945v1 111/12/5610    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hipp, M. M. Articles by Brossart, P. Search for Related Content PubMed PubMed Citation Articles by Hipp, M. M. Articles by Brossart, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 21, 2007 Accepted January 10, 2008 Sorafenib but not sunitinib affects function of dendritic cells and induction of primary immune responses Madeleine M. Hipp, Norbert Hilf, Steffen Walter, Daniela Werth, Katharina M. Brauer, Markus P. Radsak, Toni Weinschenk, Harpreet Singh-Jasuja, and Peter Brossart* Department of Hematology, Oncology and Immunology, University of Tubingen, Tubingen, Germany Research and Development, Immatics Biotechnologies GmbH, Tubingen, Germany Department of Hematology and Oncology, University of Mainz, Mainz, Germany Department of Hematology and Oncology, University of Bonn, Bonn, Germany * Corresponding author; email: peter.brossart{at}ukb.uni-bonn.de. The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we analyzed the effects of both inhibitors on the immunostimulatory capacity of human DCs and the induction of primary immune responses in vivo. Sorafenib but not sunitinib inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, MHC and costimulatory molecules in response to TLR ligands, as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated via inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on CTL induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA257-264 peptide. Sorafenib application, but not sunitinib, significantly reduced the induction of antigen specific T cells. Interestingly, numbers of regulatory T cells were reduced in PBMCs from mice treated with sunitinib. In summary, our results indicate that sunitinib, but not sorafenib is suitable for combination with immunotherapeutic approaches for treatment of cancer patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. P. Arnault, J. Wechsler, B. Escudier, A. Spatz, G. Tomasic, V. Sibaud, S. Aractingi, J.-D. Grange, V. Poirier-Colame, D. Malka, et al. Keratoacanthomas and Squamous Cell Carcinomas in Patients Receiving Sorafenib J. Clin. Oncol., August 10, 2009; 27(23): e59 - e61. [Full Text] [PDF] J.-Y. Liu, S.-H. Park, C. Morisseau, S. H. Hwang, B. D. Hammock, and R. H. Weiss Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo Mol. Cancer Ther., August 1, 2009; 8(8): 2193 - 2203. [Abstract] [Full Text] [PDF] J. Ozao-Choy, G. Ma, J. Kao, G. X. Wang, M. Meseck, M. Sung, M. Schwartz, C. M. Divino, P.-Y. Pan, and S.-H. Chen The Novel Role of Tyrosine Kinase Inhibitor in the Reversal of Immune Suppression and Modulation of Tumor Microenvironment for Immune-Based Cancer Therapies Cancer Res., March 15, 2009; 69(6): 2514 - 2522. [Abstract] [Full Text] [PDF] J. S. Ko, A. H. Zea, B. I. Rini, J. L. Ireland, P. Elson, P. Cohen, A. Golshayan, P. A. Rayman, L. Wood, J. Garcia, et al. Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients Clin. Cancer Res., March 15, 2009; 15(6): 2148 - 2157. [Abstract] [Full Text] [PDF] R. Houben, H. Voigt, C. Noelke, V. Hofmeister, J. C. Becker, and D. Schrama MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib Mol. Cancer Ther., February 1, 2009; 8(2): 433 - 440. [Abstract] [Full Text] [PDF] L. Zitvogel and G. Kroemer The dilemma of anticancer therapy: tumor-specific versus immune effects Blood, December 1, 2008; 112(12): 4364 - 4365. [Full Text] [PDF] J. H. Finke, B. Rini, J. Ireland, P. Rayman, A. Richmond, A. Golshayan, L. Wood, P. Elson, J. Garcia, R. Dreicer, et al. Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients Clin. Cancer Res., October 15, 2008; 14(20): 6674 - 6682. [Abstract] [Full Text] [PDF]

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