Antimetastatic vaccination of tumor-bearing mice with two types of IFN-γ gene-inserted tumor cells

IFN-γ genes were introduced through retroviral vectors into the high metastatic, low H-2K^b class I expressor, and poorly immunogenic 3LL-D122 clone. Two types of IFN-γ infectants were isolated: IFN-γ high secretors (128 to 256 IU/ml) and IFN-γ non- or very low secretors (<2 IU/ml). Both manifested high expression of MHC class I Ag. IFN-γ secretors showed significant decrease in tumorigenicity and metastatic growth, whereas IFN-γ nonsecretors retain tumorigenicity and were more metastatic than parental D122 cells. However, both groups, when inoculated in an irradiated form, induced similar high levels of CTL and protected mice to the same degree against a subsequent graft of parental cells. This indicates that enhanced expression of MHC class I and related genes caused by IFN-γ is the major participant in CTL induction. Immunization of mice carrying an established tumor of parental D122 cells with IFN-γ infectants is capable of almost completely preventing lung metastasis. Immunotherapy of tumor-bearing hosts is more effective when IFN-γ secreting cells are used as immunogens, indicating that mechanisms, in addition to CTL, are stimulated by secreted IFN-γ. Moreover, immunization with IFN-γ high secretors of postoperative mice, carrying established micrometastases, almost completely cured these mice. Support for the participation of non-T cell effectors in the response to IFN-γ secretors derives from the reduced tumorigenicity of these cells in CD1 nude mice. These data provide a rationale for the use of IFN-γ gene- transferred tumor cells as a modality for cancer therapy.