Subtherapeutic doses of interleukin-15 augment the anti-tumor effect of interleukin-12 in a B16F10 melanoma model in mice

Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that exhibits antitumor activity in many experimental tumor models. In the present study, we investigated the ability of IL-15, a cytokine sharing many functions of IL-2, to modulate antitumor effectiveness of IL-12 against B16F10 melanoma in mice. In a model of locally growing tumor, intratumoral (i.t.) administ ration of IL-12, in three cycles of five consecutive daily injections (0.1 mu g) followed by 2 days of rest, led to considerable delay of tumor develo pment but no curative response was achieved, When combined with IL-12, subt herapeutic doses of IL-15 (0.4 mu g) pontentiated the antitumor effects of IL-12 and induced complete tumor regressions in 50% of mice, Similar result s were obtained in a model in which tumor-bearing mice were intravenously c o-injected with melanoma cells to induce metastases, Combined administratio n of IL-12 and IL-15 yielded greater antitumor activity than injections of either cytokine alone and resulted in prolonged survival of mice bearing lo cally growing tumor and metastases, Studies of immunological parameters in mice treated with both IL-12 and IL-15 have shown enhanced NK activity (aga inst YAC-1 cells) in the spleen and stimulation of both NK activity and spe cific anti-B16F10 cytotoxic effector cells in tumor-draining lymph nodes (L N), The strong antitumor effect of the IL-12 + IL-15 combination correlated with a high serum level of IFN-gamma)I in the treated mice, Moreover, incr eased expression of IL15R alpha was demonstrated in LN lymphocytes isolated from mice injected with IL-12. This result together with findings of other authors showing enhanced expression of IL-12 receptor by IL-15 [1] suggest s that the augmentation of the antitumor effect during the course of IL-12/ IL-15-based therapy could result from reciprocal upregulation of receptors by both cytokines and synergistic effects on IFN-gamma induction.