Effective immunization against neuroblastoma using double-transduced tumor cells secreting GM-CSF and interferon-γ

Maria A. Bausero, Angela Panoskaltsis-Mortari, Bruce R. Blazar, Emmanuel Katsanis

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector MFG-granulocyte-macrophage colony-stimulating factor (GM-CSF), to examine immune stimulation conferred by localized GM-CSF production. Expression of murine GM-CSF by neuro-2a (N-2a/GM) significantly reduced its tumorigenicity. Moreover, immunization of mice with irradiated N-2a/GM cells resulted in a significant protective effect against live tumor challenge 14 days later. Approximately 41% of mice immunized with irradiated N-2a/GM versus 0% of those vaccinated with irradiated parental tumor survived. Surviving mice were rechallenged after 50 days with wild-type neuro-2a or with the Sa1 syngeneic sarcoma to discern whether the generated immunity was durable and tumor specific. All mice survived wild-type neuro-2a challenge, whereas none survived inoculation with Sa1. Because both CD4+ and CD8+ T cells were necessary during priming to this MHC class I(lo), II+ tumor, these data indicate that major histocompatibility complex (MHC) class I+, II+ antigen- presenting cells (APCs) were required for the T-cell antitumor response. Coexpression of GM-CSF and IFN-γ, both of which have immunostimulatory activities on antigen-presenting cells, abrogated the tumorigenic potential of this tumor and increased immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of mice with preexisting retroperitoneal tumors with irradiated N-2a/GM and irradiated N-2a/IFN/GM improved survival. There was a trend for nonirradiated transduced cells to be more immunogenic than their irradiated counterparts. Immunohistochemistry of tissues from the vaccination site revealed a pronounced macrophage infiltration associated with nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that vaccination involving nonirradiated neuroblastoma cells transduced with genes that stimulate APCs may be a useful approach in stimulating antitumor T-cell responses.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalJournal of Immunotherapy
Volume19
Issue number2
DOIs
StatePublished - 1996

Keywords

  • GM-CSF
  • IFN-γ
  • Immunization
  • Mice
  • Neuroblastoma

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