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* Institut National de la Santé et de la Recherche Médicale, Unité 805, Villejuif, France;
Institut Gustave Roussy and
Center of Clinical Investigations CBT507, Villejuif, France;
University Paris-Sud, Le Kremlin-Bicêtre, France;
¶ Centre National de la Recherche Scientifique, Immunologie et Embryologie Moléculaire 2815, Institut Transgénose, Orléans, France;
|| Section of General Pathology and Immunology, University of Brescia, Brescia, Italy;
# Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, Italy;
** Miltenyi Biotec GmbH, Bergisch Gladbach, Germany;
Universitätsklinikum Regensburg, Abteilung für Nephrologie, Regensburg; and
* Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany
The synergistic antitumor effects of the combination therapy imatinib mesylate (IM) and IL-2 depended upon NK1.1- expressing cells and were associated with the accumulation of CD11cintB220+NK1.1+ IFN-producing killer dendritic cells (IKDC) into tumor beds. In this study, we show that the antitumor efficacy of the combination therapy was compromised in IL-15 and IFN-type 1R loss-of-function mice. IL-15R
was required for the proliferation of IKDC during IM plus IL-2 therapy. Trans-presentation of IL-15/IL-15R activated IKDC to express CCR2 and to respond to type 1 IFN by producing CCL2. Moreover, the antitumor effects of the combination therapy correlated with a CCL2-dependent recruitment of IKDC, but not B220– NK cells, into tumor beds. Altogether, the IL-15-driven peripheral expansion and the CCL-2-dependent intratumoral chemoattraction of IKDC are two critical parameters dictating the antitumor efficacy of IM plus IL-2 in mice.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by European Union grants (ALLOSTEM, DC THERA), Association pour la Recherche sur le Cancer, and Ligue Nationale Contre le Cancer (équipes labelisées de G. Kroemer and L.Z.). G.M. was supported by the Association pour la Recherche sur le Cancer, E.U. received a fellowship from the Deutsche Forschungsgemeinschaft and from the Fondation pour la Recherche Médicale, and M.B. was supported by the Poste d’Accueil Institut National de la Santé et de la Recherche Médicale.
2 G.M. and E.U. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Nathalie Chaput, Center of Clinical Investigations CBT507, Institut National de la Santé et de la Recherche Médicale Unité 805, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail address: nathalie.chaput{at}igr.fr
4 Abbreviations used in this paper: IM, imatinib mesylate; DC, dendritic cell; IKDC, IFN-producing killer DC; pDC, plasmacytoid DC; rh, recombinant human; bid, twice a day; CTX, cyclophosphamide; ODN, oligodeoxynucleotide; WT, wild type; cDC, conventional DC.
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