PT  - JOURNAL ARTICLE
AU  - Zeng, Yan
AU  - Huebener, Nicole
AU  - Fest, Stefan
AU  - Weixler, Silke
AU  - Schroeder, Ulrike
AU  - Gaedicke, Gerhard
AU  - Xiang, Rong
AU  - Schramm, Alexander
AU  - Eggert, Angelika
AU  - Reisfeld, Ralph A.
AU  - Lode, Holger N.
TI  - Fractalkine (CX3CL1)– and Interleukin-2–Enriched Neuroblastoma Microenvironment Induces Eradication of Metastases Mediated by T Cells and Natural Killer Cells
AID  - 10.1158/0008-5472.CAN-06-3041
DP  - 2007 Mar 01
TA  - Cancer Research
PG  - 2331--2338
VI  - 67
IP  - 5
4099  - http://cancerres.aacrjournals.org/content/67/5/2331.short
4100  - http://cancerres.aacrjournals.org/content/67/5/2331.full
SO  - Cancer Res2007 Mar 01; 67
AB  - 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 TH1 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-γ 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. [Cancer Res 2007;67(5):2331–8] ©2007 American Association for Cancer Research.