Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

The central nervous system shows tolerance for activated host immune reacti ons, and this relative unresponsiveness may lessen the efficacy of an immun otherapy for brain tumors. Using interleukin-2 (IL-2)-producing 9L rat glio sarcoma cells (9L/IL-2), we examined whether secretion of IL-2 from subcuta neous (s.c.) and/or intracerebral (i.c.) tumors can elicit augmented immuno logical responses to brain tumors. Syngeneic rats could reject 9L/IL-2 cell s inoculated s.c., but developed 9L/IL-2 brain tumors by i.c. inoculation. The growth of i.c. 9L/IL-2 tumors was, however, significantly retarded comp ared with that of i.c. wild-type tumors. The growth of i.c. wild-type tumor s was significantly suppressed when the rats concurrently received 9L/IL-2 cells s.c. Moreover, most of the rats that were inoculated i.c. with 9L/IL- 2 cells did not develop brain tumors when concurrently injected s.c. with 9 L/IL-2 cells. Immunohistochemical analysis on i.c. 9L/IL-2 tumors, when the rats were concurrently inoculated s.c. with 9L/IL-2 cells, revealed that m igration of CD4(+) or CD8(+) T cells, monocytes/microglias, and macrophages was markedly augmented to a similar level as found in the s.c. 9L/IL-2 tum ors. These results showed that systemic immune responses to brain tumor wer e induced in an immunologically privileged site by concurrent s.c. inoculat ion of the same tumors that produce IL-2. The present study may also raise the possibility of a therapeutic strategy for brain tumors by the combinato ry expression of IL-2 gene using s.c. immunization followed by direct gene transfer into brain tumors.