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

Grégoire Mignot (1, 2, 3) , Evelyn Ullrich (1, 2, 3) , Mathieu Bonmort (1, 2, 3) , Cédric Ménard (1, 2, 3) , Lionel Apetoh (1, 2, 3) , Julien Taieb (1) , Daniela Bosisio (3) , Silvano Sozzani (4) , Maria Ferrantini (5) , Jürg Schmitz (6) , Matthias Mack (7) , Bernhard Ryffel (8) , Silvia Bulfone-Paus (1) , Laurence Zitvogel (1, 2, 3, 9) , Nathalie Chaput (1, 2, 9)

1 Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale
2 IGR - Institut Gustave Roussy
3 UP11 - Université Paris-Sud - Paris 11
4 GPI - General Pathology and Immunology
5 CBN - Cell Biology and Neuroscience
6 Miltenyi Biotec Gmbh
7 Abteilung für Nephrologie
8 IEM - Immunologie et Embryologie Moléculaires
9 CCI - Center of Clinical Investigations CBT507

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.

Domaines: Immunologie

Grégoire Mignot, Evelyn Ullrich, Mathieu Bonmort, Cédric Ménard, Lionel Apetoh, et al.. The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2.. Journal of Immunology, 2008, 180 (10), pp.6477-83. ⟨hal-00364426⟩