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

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.