TRANSDUCTION OF HUMAN-MELANOMA CELLS WITH THE GAMMA-INTERFERON GENE ENHANCES CELLULAR-IMMUNITY

Human tumor cells transduced with the gamma interferon (gamma IFN) gen e are currently used in specific active immunotherapy protocols to enh ance the antitumor immune responses of cancer patients. This in vitro study was undertaken to examine the initial events in the cellular imm une response that may occur following the administration of the gamma IFN-transduced cell vaccine. Human melanoma tumor cell lines were tran sduced with a MoMLV-based retroviral vector carrying the human gamma l FN gene. The transduced cells expressed the cytokine gene, secreted bi ologically active gamma IFN, and exhibited enhanced expression of MHC class I and class II (HLA-DR), and ICAM-1 surface antigens. The gamma IFN-transduced and corresponding parental melanoma cells were used for the induction of short-term lymphocyte cultures. Peripheral blood lym phocytes or lymph node cells from 20 melanoma patients were stimulated for 5 to 15 days with autologous or MHC class I-matched allogeneic pa rental or gamma IFN-transduced melanoma cells. Seven of the 20 lymphoc yte cultures showed substantial increases in lytic activity following stimulation with the transduced melanoma cells in comparison to contro l lymphocyte cultures stimulated with unmodified parental melanoma. Th e cytolytic activity stimulated with gamma IFN-modified melanomas was mediated partly by MHC-restricted cytotoxic T lymphocytes and partly b y NK cells. Lymphocyte cultures that displayed increases in cytotoxici ty after stimulation with the gamma IFN-transduced melanoma cells also exhibited enhanced expression or induction of one or more of the foll owing lymphokines: IL-4, IL-1 alpha, IL-1 beta, gamma IFN, and TNF-alp ha. Under these conditions of short-term cultures, the clonal expansio n of lymphocytes stimulated with the gamma IFN-modified cells increase d an average of 1.7-fold over control cultures stimulated with parenta l cells. The data provide a rationale for the use of gamma IFN-modifie d cells as a vaccine for melanoma patients and as an immunogen for the induction of effector cells for adoptive immunotherapy of malignant m elanoma.