Fractalkine (CX3CL1)–and interleukin-2–enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells
Y Zeng, N Huebener, S Fest, S Weixler… - Cancer …, 2007 - aacrjournals.org
Y Zeng, N Huebener, S Fest, S Weixler, U Schroeder, G Gaedicke, R Xiang, A Schramm…
Cancer research, 2007•aacrjournals.orgFractalkine (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 …
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 …
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 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]
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