title: Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells.
abstract: Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by T(H)1 immune cells including T cells and natural killer (NK) cells. FKN was shown to be expressed in >90% of 68 neuroblastoma samples as determined by cDNA microarray analysis. Here, we characterized the effect of FKN in the neuroblastoma microenvironment using a syngeneic model genetically engineered to secrete FKN. We show FKN-mediated migration, adhesion, and IFN-gamma secretion of immune effector cells, but limited antineuroblastoma activity, in vitro and in vivo. Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. For this purpose, IL-2 was targeted to ganglioside GD2, which is highly expressed on neuroblastoma tissue, using an anti-GD2 antibody IL-2 immunocytokine (ch14.18-IL-2). Only mice bearing FKN- and IL-2-enriched neuroblastoma tumors exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN- and IL-2-enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. In summary, we showed for the first time the immunologic mechanisms by which targeted IL-2 treatment of neuroblastoma with an FKN-rich microenvironment induces an effective antitumor response.
authors.affiliation: Pediatrics, Experimental Oncology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Nicole
authors.initials: N
authors.lastname: Huebener
authors.forename: Stefan
authors.initials: S
authors.lastname: Fest
authors.forename: Silke
authors.initials: S
authors.lastname: Weixler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schroeder
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; D007376:Interleukin-2; D008565:Membrane Proteins