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

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-gamma 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-gamma 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. Copyright 2000 Wiley-Liss, Inc.