VACCINATION WITH IL-2-SECRETING TUMOR-CELLS STIMULATES THE GENERATIONOF IL-2-RESPONSIVE T-CELLS AND PREVENTS THE DEVELOPMENT OF UNRESPONSIVENESS

Infection of CMS5 tumor cells with retroviral constructs containing in terleukin-2 (IL-2) cDNA and selection in medium supplemented with G418 resulted in the isolation of clones which secreted IL-2. Whereas inje ction of parental tumor cells resulted in progressive tumor growth, tu mor cells secreting high levels of IL-2 were rejected. Furthermore in animals vaccinated with IL-2-secreting cells, the immunosuppression as sociated with the inoculation of parental tumor cells did not develop, and these animals resisted a challenge with viable tumor cells. To be tter understand the functional differences in the anti-tumor responses of immune and tumor-bearing mice which are at the basis for these div erse responses, we used an in vitro model to analyze interactions betw een splenic lymphocytes and tumor cells. Spleen cells isolated from ei ther tumor-bearing or immune mice proliferated vigorously when culture d alone for 6 days, but much less in the presence of parental tumor ce lls. This effect could not be transferred with supernatant from tumor cell lines. Spleen cells from tumor-bearing mice remained unresponsive , while those from immune mice proliferated well in response to IL-2-s ecreting tumor cells. Only spleen cells from immune animals were able to develop cytotoxicity against CMS5 cells following in vitro restimul ation. These results are consistent with the interpretation that expos ure to parental tumor cells inhibited cell-mediated anti-tumor respons es by a mechanism that involved cell-to-cell contact. Furthermore, the development of this inhibition was dependent on a failure of respondi ng cells to generate sufficient amounts of IL-2, since it could be pre vented or overcome, at least in part, by locally secreted IL-2.