Gene transfer of a secretable form of IL-15 in murine adenocarcinoma cells: Effects on tumorigenicity, metastatic potential and immune response

Raffaella Meazza, Pier Luigi Lollini, Patrizia Nanni, Carla De Giovanni, Alessia Gaggero, Alberto Comes, Michele Cilli, Emma Di Carlo, Silvano Ferrini, Piero Musiani

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Abstract

IL-15 is an immunostimulatory cytokine with IL-2-like activities. To exploit the potential role of IL-15 in cancer immuno-/gene therapy, we engineered murine TS/A cells with different IL-15 cDNA constructs. Significant IL-15 secretion was achieved only by the use of a modified cDNA encoding for an IL-15 pre-protein bearing the IgK light chain signal peptide. Different TS/A clones (TS/A IL-15 C6, C23, C29) producing 390 to 1,600 pg/ml biologically active IL-15 showed reduced tumorigenicity when implanted s.c. in syngeneic mice and significantly reduced metastatic potential by i.v. injection. Tumorigenicity of s.c. TS/A IL-15 was restored in animals depleted of CD8+ lymphocytes or of natural killer cells and partially in CD4+-depleted mice. TS/A IL-15 cells displayed a significantly reduced growth rate by s.c. implant in nude mice. Also, >50% syngeneic animals rejecting TS/A IL-15 were resistant to a subsequent rechallenge with wild type tumor (TS/Apc), indicating induction of protective immunity against TS/A tumor-associated antigens (TAAs). Cytolytic T lymphocyte (CTL) activity, specifically inhibited by anti-CD3 antibodies, was inducible in the splenocytes of TS/A IL-15-immunized animals by mixed lymphocyte/tumor culture (MLTC), and IFN-γ was released in the supernatant of MLTC, mainly by CD8+ cells. Immunohistochemistry of the TS/A IL-15 tumor area revealed the presence of an inflammatory infiltrate with predominant natural killer, macrophage, and granulocyte components and expression of IFN-γ as a distinctive secondary cytokine. Use of TS/A IL-15 mitomycin-treated cells for therapeutic vaccination in experimental TS/A metastasis was effective in 60% of animals treated; these animals showed no metastatic tumor growth. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)574-581
Number of pages8
JournalInternational Journal of Cancer
Volume87
Issue number4
Publication statusPublished - 2000

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Meazza, R., Lollini, P. L., Nanni, P., De Giovanni, C., Gaggero, A., Comes, A., Cilli, M., Di Carlo, E., Ferrini, S., & Musiani, P. (2000). Gene transfer of a secretable form of IL-15 in murine adenocarcinoma cells: Effects on tumorigenicity, metastatic potential and immune response. International Journal of Cancer, 87(4), 574-581.