Abstract
9521 Background: Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form. Methods: We found that FKN is expressed in >90% of 68 neuroblastoma (NB) samples as determined by cDNA microarray analysis. FKN expression was inversely correlated with MYCN amplification, suggesting a higher expression of FKN in MYCN non amplified tumors. We characterized the effect of FKN in the neuroblastoma microenvironment in a mouse model. We demonstrate that FKN released from NB cells mediate migration and adhesion of CD4+-, CD8+- and NK- cells and subsequent secretion of IFN-γ, in vitro and in vivo. However, the presence of FKN in NB microenvironments did not result in significant anti-NB activity. Results: Targeting of IL-2 into the NB microenvironment using anti-ganglioside GD2 antibody cytokine fusion proteins (ch14.18-IL-2) is currently under clinical evaluation. We investigated a the role of FKN in this context. For this purpose, IL-2 was targeted to GD2 positive NB microenvironments secreting FKN. Only mice bearing FKN and IL2 enriched NB microenvironments exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases, in contrast to controls with only FKN or IL-2 enriched NB. This effect was specific since a non-specific antibody-IL-2 fusion protein ch225-IL-2 was ineffective. The mechanisms involved included NK-cell activation by targeted IL-2 into FKN rich NB as indicated by the enhancement of NK-cell mediated lysis using YAC-1 cells as targeted cells. The depletion of NK cells in vivo inhibited the therapeutic effect. Furthermore, co-culture of NXS2-FKN cells and NK cells in vitro induced the expression of IFN-γ by NK cells. However, the depletion of CD8+ T-cells in vivo abrogated the therapeutic effect, and these effector cells showed the highest cytolytic activity against NXS2 target cells in vitro. Finally, only the FKN and IL-2 enriched NB microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. Conclusions: In conclusion our data suggest that targeted IL-2 therapy of FKN rich NB associated with MYCN non-amplified tumors may result in T-cell mediated immune responses. No significant financial relationships to disclose.
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