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

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.
J Immunol. 2008 May 15;180(10):6477-83.

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.

URL: http://www.jimmunol.org/cgi/content/full/180/10/6477

Pub Med: http://www.ncbi.nlm.nih.gov/pubmed/18453565

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