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(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.
Mignot
Grégoire
G
Institut National de la Santé et de la Recherche Médicale, Unité 805, Villejuif, France.
Ullrich
Evelyn
E
Bonmort
Mathieu
M
Ménard
Cédric
C
Apetoh
Lionel
L
Taieb
Julien
J
Bosisio
Daniela
D
Sozzani
Silvano
S
Ferrantini
Maria
M
Schmitz
Jürg
J
Mack
Matthias
M
Ryffel
Bernard
B
Bulfone-Paus
Silvia
S
Zitvogel
Laurence
L
Chaput
Nathalie
N
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D018932:Chemokine CCL2 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D019409:Interleukin-15 / Q000276:immunology*; D007376:Interleukin-2 / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D054390:Receptors, CCR2 / Q000378:metabolism; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism; D000096743:Interferon gamma Receptor
D001549:Benzamides; D018932:Chemokine CCL2; D000068877:Imatinib Mesylate; D019409:Interleukin-15; D007376:Interleukin-2; D010879:Piperazines; D011743:Pyrimidines; D054390:Receptors, CCR2; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse