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

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

Edité par CCSD ; Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists -

International audience. 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(int)B220(+)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-15Ralpha was required for the proliferation of IKDC during IM plus IL-2 therapy. Trans-presentation of IL-15/IL-15Ralpha 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.

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