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Antitumor and Immunotherapeutic Effects of Activated Invasive T Lymphoma Cells That Display Short-Term Interleukin 1 Expression¹

Departments of Microbiology and Immunology [E. V., Y. W., R. O., M. D., R. M. W., S. S., R. N. A.] and Pathology [D. B., E. C.], Faculty of Health Sciences, and The Cancer Center [E. V., Y. W., R. O., M. D., R. M. W., S. S., R. N. A.], Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; The German Cancer Research Center (Deutsches Krebsforschungscentrum), Heidelberg D-69120, Germany [M. Z.]; and Department of Oncology, Hadassah University Hospital, Jerusalem, 91120, Israel [V. B.]

Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1 (IL-1) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1 by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1. The short-term expression of IL-1 persists in the malignant T cells for a few days (3–6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1 in a short-term manner, manifested reduced tumorigenicity: 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1 in activated tumor cells may allow its improved application in the treatment of malignancies.

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