Interleukin-2 gene transfer into murine neuroblastoma decreases tumorigenicity and enhances systemic immunity causing regression of preestablished retroperitoneal tumors.
Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector LIL-2SN in order to examine the influence of localized interleukin (IL)-2 production on the immune response against a low major histocompatibility complex (MHC) class I, class II-negative, and intercellular adhesion molecule (ICAM)-1-negative tumor. Two neomycin-resistant (neo R) clones, N-2a/IL-2/L (2.5 +/- 0.4 U/ml/10(6) cells/24 h) and N-2a/IL-2/H (44.6 +/- 8.8 U/ml), were studied as representative low and high IL-2 producers, respectively. Using a recently developed retroperitoneal (r.p.) model for implantation of neuroblastoma in its natural site, we demonstrated that production of IL-2 by neuro-2a reduces its tumorigenicity in a dose-dependent fashion. T-cell, but not natural killer (NK) cell, depletion significantly increased tumor induced mortality in syngeneic A/J mice. Mice genetically devoid of T-cells (C.B-17 scid/scid) also experienced a significant increase in mortality rates. This indicates that the antitumor effect of locally secreted IL-2 is mediated primarily through activation of T-cells. Immunization of mice with irradiated N-2a/IL-2/H cells resulted in protection when challenged at a later date with unmodified neuro-2a cells. Depletion of CD8+, but not CD4+, T-cells prior to vaccination abrogated the protective effect, indicating that the priming phase of the immune response is CD8+ T-cell dependent. Mice with established r.p. tumors were vaccinated with N-2a/IL-2/H, which significantly prolonged their survival compared to unimmunized controls and to mice immunized with non-IL-2-producing neuro-2a cells. Because of the similarities of this model with the human tumor, our studies indicate that IL-2-transduced neuroblastoma cells may be effective in generating systemic immunity leading to eradication of minimal residual disease.
Katsanis
E
E
Department of Pediatrics, University of Minnesota, Minneapolis 55455.
Orchard
P J
PJ
Bausero
M A
MA
Gorden
K B
KB
McIvor
R S
RS
Blazar
B R
BR
D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D005260:Female; D018014:Gene Transfer Techniques; D007114:Immunization; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000276:immunology* / Q000628:therapy; D012186:Retroperitoneal Neoplasms / Q000276:immunology* / Q000628:therapy; D014407:Tumor Cells, Cultured
D007376:Interleukin-2