The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2

Grégoire Mignot, Evelyn Ullrich, Mathieu Bonmort, Cédric Ménard, Lionel Apetoh, Julien Taieb, Daniela Bosisio, Silvano Sozzani, Maria Ferrantini, Jürg Schmitz, Matthias Mack, Bernard Ryffel, Silvia Bulfone-Paus, Laurence Zitvogel, Nathalie Chaput

Research output: Contribution to journalArticle

Abstract

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 CD11c intB220 +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-15Rα was required for the proliferation of IKDC during IM plus IL-2 therapy. Trans-presentation of IL-15/IL-15Rα activated IKDC to express CCR2 and to respond to type 1IFN 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 INI plus IL-2 in mice.

Original languageEnglish
Pages (from-to)6477-6483
Number of pages7
JournalJournal of Immunology
Volume180
Issue number10
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Immunology

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    Mignot, G., Ullrich, E., Bonmort, M., Ménard, C., Apetoh, L., Taieb, J., Bosisio, D., Sozzani, S., Ferrantini, M., Schmitz, J., Mack, M., Ryffel, B., Bulfone-Paus, S., Zitvogel, L., & Chaput, N. (2008). The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2. Journal of Immunology, 180(10), 6477-6483.