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: Yan Zeng, Nicole Huebener, Stefan Fest, Silke Weixler, Ulrike Schroeder, Gerhard Gaedicke, Rong Xiang, Alexander Schramm, Angelika Eggert, Ralph A Reisfeld, Holger N Lode
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 5 Pg. 2331-8 (Mar 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17332365 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CX3CL1 protein, human
• Chemokine CX3CL1
• Chemokines, CX3C
• Cx3cl1 protein, mouse
• Interleukin-2
• Membrane Proteins

Topics

• Animals
• Cell Line, Tumor
• Chemokine CX3CL1
• Chemokines, CX3C (genetics, metabolism, physiology)
• Female
• Gene Targeting
• Humans
• Immunity, Cellular
• Immunotherapy (methods)
• Interleukin-2 (genetics, therapeutic use)
• Killer Cells, Natural (immunology)
• Membrane Proteins (genetics, metabolism, physiology)
• Mice
• Mice, Inbred Strains
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neuroblastoma (immunology, metabolism, pathology, therapy)
• T-Lymphocytes (immunology)