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Enhanced Expression of HLA Molecules and Stimulation of Autologous Human Tumor Infiltrating Lymphocytes Following Transduction of Melanoma Cells with -Interferon Genes

Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892

Gene therapy for cancer is being tested in clinical trials using tumor-infiltrating lymphocytes (TIL) or tumor cells modified by the insertion of genes coding for interleukin 2 or tumor necrosis factor . In the present study, we investigated the feasibility of transducing human tumor cells with genes coding for -interferon (IFN) or -interferon (IFN), which are two other cytokines that can enhance host antitumor immune responses.

Tumor cells from 12 melanoma and 2 renal cell carcinoma patients were transduced with retroviral vectors containing the gene for IFN. Northern blot analysis showed IFN transcripts only in the IFN gene-transduced cells. In both IFN-secreting and non-secreting tumor lines, the cell surface expression of HLA class I and class II molecules increased following transduction. However, the magnitude of the increase in HLA expression appeared to be greater in tumor lines secreting IFN.

Two melanoma cell lines were successfully transduced with an IFN retroviral vector. Melanoma cells transduced with the IFN gene contained IFN RNA transcripts and secreted large amounts of IFN. In contrast to cells transduced with the IFN gene, the expression of HLA class II molecules was not increased in the IFN gene-transduced cells.

Finally, we tested the ability of HLA.DR⁺ melanoma cells, which had been transduced with the IFN gene, to stimulate specific cytokine release by autologous CD4⁺ TIL. Specific secretion of cytokine by TIL occurred when the TIL and IFN gene-transduced tumor cells were cultured together but not when TIL were cultured alone or with control nontransduced tumor cells. These results suggest that molecules newly expressed on the transduced cells promoted antigen presentation and T-cell responses against the transduced tumor cells. The insertion of the IFN gene into melanoma cells may be useful either for active immunization against melanoma or for the generation of TIL to be used in adoptive immunotherapy.

Received 3/ 2/93. Accepted 5/20/93.

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