Vaccination with B16 melanoma cells expressing a secreted form of interleukin-1beta induces tumor growth inhibition and an enhanced immunity against the wild-type B16 tumor.

We have demonstrated previously that gene transfer of the mature human interleukin-1beta (IL-1beta) gene, fused to a signal sequence (ss), into mouse B16 melanoma cells results in an inhibition of their growth in vivo compared with control B16 cells. We here extend these results to show that intraperitoneal vaccinations with irradiated IL-1beta-secreting cells result in protection against subsequent subcutaneous challenge with wild-type (wt) B16 tumor cells in syngeneic C57BL/6 mice. This protection appears to be long-lasting, because rechallenge of cured mice 4 months after the first challenge also demonstrated resistance. In addition, we demonstrate that mice with established wt tumors subjected to therapeutic vaccinations with irradiated B16/ssIL-1beta cells starting 3 days after challenge isografting have a significantly inhibited tumor growth and 25-40% survival at the challenge doses given. In vitro coculture of spleen cells from B16/ssIL-1beta vaccinated animals and wt B16 cells induced an enhanced proliferative response, which correlated with elevated production of IL-2 and interferon-gamma. A significantly enhanced cytolytic activity against B16 wt target tumor cells was observed when spleen cells from B16/ssIL-1beta vaccinated mice were used as effector cells compared with spleen cells from control vaccinated mice. In vitro depletion experiments using anti-asialo GM1 revealed a prominent role for natural killer cells as effector cells. The data suggest that local IL-1beta secretion during the vaccination phase can provoke or augment protective immune responses to B16 melanoma cells, which are otherwise not recorded in mice bearing B16 tumors.