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

Witold Lasek, Jakub Golłab, Włodzimierz Maśliński, Tomasz Świtaj, Ewa Z. Bałkowiec, Tomasz Stokłosa, Adam Giermasz, Magdalena Malejczyk, Marck Jakóbisiak

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25 Scopus citations

Abstract

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.) administration of IL-12, in three cycles of five consecutive daily injections (0.1 μg) followed by 2 days of rest, led to considerable delay of tumor development but no curative response was achieved. When combined with IL-12, subtherapeutic doses of IL-15 (0.4 μg) pontentiated the antitumor effects of IL-12 and induced complete tumor regressions in 50% of mice. Similar results were obtained in a model in which tumor-bearing mice were intravenously co-injected with melanoma cells to induce metastases. Combined administration of IL-12 and IL-15 yielded greater antitumor activity than injections of either cytokine alone and resulted in prolonged survival of mice bearing locally growing tumor and metastases. Studies of immunological parameters in mice treated with both IL-12 and IL-15 have shown enhanced NK activity (against YAC-1 cells) in the spleen and stimulation of both NK activity and specific anti-B16F10 cytotoxic effector cells in tumor-draining lymph nodes (LN). The strong antitumor effect of the IL-12 + IL-15 combination correlated with a high serum level of IFN-γ in the treated mice. Moreover, increased expression of IL-15Rα 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 suggests 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-γ induction.

Original languageEnglish (US)
Pages (from-to)345-356
Number of pages12
JournalEuropean Cytokine Network
Volume10
Issue number3
StatePublished - 1999
Externally publishedYes

Keywords

  • Interleukin-12
  • Interleukin-15
  • Tumor immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Clinical Biochemistry

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    Lasek, W., Golłab, J., Maśliński, W., Świtaj, T., Bałkowiec, E. Z., Stokłosa, T., Giermasz, A., Malejczyk, M., & Jakóbisiak, M. (1999). Subtherapeutic doses of interleukin-15 augment the anti-tumor effect of interleukin-12 in a B16F10 melanoma model in mice. European Cytokine Network, 10(3), 345-356.