Immunotherapy via gene therapy: comparison of the effects of tumor cells transduced with the interleukin-2, interleukin-6, or interferon-gamma genes.
We have comparatively analyzed the immune mechanisms induced by and the immunotherapeutic potentials of a highly metastatic clone of the Lewis lung carcinoma, D122, transduced with the interleukin-2 (IL-2), IL-6, or interferon-gamma (IFN-gamma) genes. All of the D122 cytokine gene-transduced cells induced antitumor CD8+ cytotoxic T lymphocytes (CTLs), as can be judged from in vivo depletion of CD8+ cells and in vitro CTL assays. In vivo depletion of CD4+ cells did not affect the malignant phenotypes of the different D122 gene-modified cells, but in vivo depletion of natural killer (NK) cells resulted in increased malignancy of both D122 cells and D122 gene-modified cells. In accordance with the effects of in vivo NK depletion, D122 as well as D122 derivative cells were sensitive to lysis by polyinosinic-polycytidylic acid (poly I:C)-induced activity. We discuss the immune responses generated by the different D122 gene-modified cells in view of their in vivo behavior in syngeneic and nude mice. We also performed comparative analysis of the capacity of vaccinations with irradiated D122 gene-modified cells to cure established micrometastases of parental D122 cells in tumor-operated mice. Vaccinations with D122-IL-2 or -IL-6 secretors did not generate a significant effect. Also, vaccinations with D122-IFN-gamma cells, which showed increased major histocompatibility complex class I expression but did not secrete detectable levels of IFN-gamma, did not cure established micrometastases. Only vaccination with D122-IFN-gamma high secretors efficiently cured postoperated mice carrying established micrometastases. We discuss the relevance of these results to the application of immunotherapy via cytokine gene therapy of human malignancy.
Porgador
A
A
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Tzehoval
E
E
Vadai
E
E
Feldman
M
M
Eisenbach
L
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D015850:Interleukin-6; D007371:Interferon-gamma