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Augmentation of Tumor Targeting in a Line of Glioma-specific Mouse Cytotoxic T-Lymphocytes by Retroviral Expression of Mouse -Interferon Complementary DNA¹

Department of Neurosurgery, Medical School [K. N., S. M., J. Y., H. K.], and Departments of Molecular and Cellular Virology [Y. K., Y. W.] and Pathology [Y. Z., Y. N., M. H.], Institute for Virus Research, Kyoto University, Kyoto, Japan; and Shionogi Research Laboratories, Osaka, Japan [T. S.]

As an initial approach to experiments directed toward effective adoptive immunotherapy for cancer using lymphokine genes, we transferred retrovirally a complementary DNA encoding mouse -interferon (IFN-) into a specific cytotoxic T-lymphocyte clone, designated E-4, against 203 glioma cells (a 20-methylcholanthrene-induced mouse glioma line) and confirmed the efficacy of IFN- production from the exogenous gene on augmentation of tumor targeting. Of five, two gene-transferred subclones constitutively produced 8 to 10 times the amount of IFN- as compared with the parental E-4. Correspondingly, these two subclones exhibited 2 to 3 times higher killing activity against 203 glioma than the parental cells; the enhancement of the killing activities was abrogated by an adequate addition of anti-IFN- antibody.

No alteration was seen after the gene transfer in cell surface phenotypes, Thy-1⁺, Lyt-1^-, Lyt-2⁺,3⁺, and asialo-G_M1^-. The surface expression of a major histocompatibility complex Class I antigen, H-2K^b, was not altered remarkably, but the Class II antigen, I-A^b, was partially and slightly enhanced on the two IFN--producing sublines mentioned above on fluorescence-activated cell sorter analysis.

Since it is considered that in the vicinity of the constitutively IFN- producing cytotoxic T-lymphocyte cells tumor cells are exposed to a high concentration of IFN-, the cells may be stimulated to induce or enhance the expression of surface antigens including major histocompatibility complex antigens as well as tumor-associated antigens relevant to immune recognition. The 203 glioma cells pretreated with IFN- were more efficiently killed by both the parental E-4 and the gene-transferred sublines.

Taken together, the results suggested that the augmented specific tumor-killing activity of our gene-transferred cytotoxic T-lymphocytes was ascribed to the constitutive production of IFN- derived from the exogenous gene.

¹ These studies were supported in part by the Grant-in-Aid for Cancer Research (61-17) from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at Kyoto University, Institute for Virus Research, Department of Molecular and Cellular Virology, 53 Shougoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan.

Received 12/ 9/87. Revised 4/26/88. Accepted 5/25/88.

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