COMBINED VACCINATION WITH MAJOR HISTOCOMPATIBILITY CLASS-I AND INTERLEUKIN-2 GENE-TRANSDUCED MELANOMA-CELLS SYNERGIZES THE CURE OF POSTSURGICAL ESTABLISHED LUNG METASTASES

We have analyzed and compared in detail the malignant phenotypes of, t he immune mechanisms induced by, and the immunotherapeutic potentials of B16-F10.9 melanoma cells manipulated by gene transfer to express sy ngeneic H-2K(b) molecules or to secrete the cytokines interleukin 2 (I L-2) or IL-6. Local tumor growth in the footpad of transduced cells is mainly retarded by expression of H-2K(b) and IL-2 genes and Less by e xpression of IL-6. Mice given injections intrafootpad of tumorigenic d oses of transduced clones manifested significantly reduced postsurgica l spontaneous metastasis. After i.v. inoculation, mice given injection s of F10.9-K-b expressors did not develop experimental lung metastases ; mice given injections of F10.9-IL-6 secretors developed reduced meta static loads; whereas mice given injections of F10.9-IL-2 secretors de veloped high loads of lung metastases. On the basis of injections into nude mice, in vivo depletions of CD4(+), CD8(+), and NK1.1(+) cells, and in vitro CTL and natural killer (NK) assays, we show that all F10. 9-modified cells induce CD8(+) tumor-specific CTL activity and that F1 0.9-IL-2 secretors also induce nonspecific NK/lymphokine-activated kil ler cell activity. Vaccinations with F10.9-modified cells were capable of significantly reducing metastatic spread from small established F1 0.9 footpad tumors. However, in mice carrying preestablished lung meta stases, a highly therapeutic effect was achieved only when H-2K(b) exp ressors and IL-2 secretors were combined in vaccination, whereas indiv idual vaccines or other combinations had marginal effects. This higher efficiency of the combined vaccine is due to the combined effect of e fficient CTL induction and NK/lymphokine-activated killer cell activit y as concluded from depletion of CD8(+) and NK1.1 cells during immunot herapy. Thus, the cure of established metastasis can be achieved by th e synergistic effects of vaccination with class I and IL-2-transduced tumor cells.