Interleukin-2 gene transfer into murine neuroblastoma decreases tumorigenicity and enhances systemic immunity causing regression of preestablished retroperitoneal tumors

Emmanuel Katsanis, Paul J. Orchard, Maria A. Bausero, Keith B. Gorden, R. Scott McIvor, Bruce R. Blazar

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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)-l-negative tumor. Two neomycin-resistant (neo R) clones, N-2a/IL-2/L (2.5 ± 0.4 U/ml/106cells/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 scidlscid) 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.

Original languageEnglish (US)
Pages (from-to)81-90
Number of pages10
JournalJournal of Immunotherapy
Volume15
Issue number2
DOIs
StatePublished - Feb 1994
Externally publishedYes

Keywords

  • Gene transfer
  • Interleukin-2
  • Neuroblastoma
  • Tumor vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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