title: The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 805, Villejuif, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bonmort
authors.forename: Cédric
authors.initials: C
authors.lastname: Ménard
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
authors.forename: Daniela
authors.initials: D
authors.lastname: Bosisio
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrantini
authors.forename: Jürg
authors.initials: J
authors.lastname: Schmitz
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Silvia
authors.initials: S
authors.lastname: Bulfone-Paus
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
mesh_terms: 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
chemical_list: 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