CHARACTERIZATION OF SPONTANEOUS MURINE ASTROCYTOMA AND ABROGATION OF ITS TUMORIGENICITY BY CYTOKINE SECRETION

OBJECTIVE: The promise of immunotherapies developed against brain tumo rs in animal models has not been realized in human clinical trials. Th io may be because of the routine use of rodent tumors artificially ind uced by chemicals or viruses that do not accurately portray the intrin sic qualities of spontaneously arising human tumors and that often fai l to incorporate the role of immunosuppressants, such as transforming growth factor-beta, that are secreted by human gliomas. From an astroc ytoma that arose spontaneously in inbred VM/Dk mice, we have character ized a highly tumorigenic spontaneous murine astrocytoma cell line (SM A-560) that retains features of glial differentiation and naturally pr oduces high levels of biologically active transforming growth factor-b eta. We have used this model to determine whether cytokine production by tumor cells will inhibit intracerebral astrocytoma growth. METHODS: Packaging cell lines producing replication-incompetent retroviral vec tors were used to transfect the SMA-560 cell line in vitro with the ge nes encoding the murine cytokines interleukin (IL)-2, IL-3, IL-4, IL-6 , tumor necrosis factor-cv, gamma-interferon, or granulocyte-macrophag e colony-stimulating factor or the costimulatory molecule B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA- 560 cells all succumbed to tumor within 30 days, with a median surviva l of 25 days. In contrast, mice challenged with SMA-560 cells producin g IL-2, IL-4, or tumor necrosis factor-alpha each had a more than 400% increase in median survival (P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and 60% (6 of 10 mice) of the mice , respectively, remained alive without evidence of tumor for longer th an 100 days after the initial tumor challenge. All other cytokines tes ted and the expression of B7.1 failed to result in an increase in medi an survival. CONCLUSION: Using a spontaneous astrocytoma model in an i nbred mouse strain, we have shown that cytokine production by glial tu mors can abrogate their tumorigenicity in vivo despite production of t ransforming growth factor-beta. These results predict that approaches directed at cytokine production within intracerebral astrocytomas may be efficacious in human trials and that the ''immunological privilege' ' of the brain may not be absolute under such conditions.