Synergistic effect of interleukin-15 and interleukin-12 on antitumor activity in a murine malignant pleurisy model

Interleukin(IL)-15, which uses IL-2 receptor (R) beta and gamma chains for signal transduction, shares many of the biological activities of IL-2. We e xamined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival t ime of mice after an intrapleural inoculation of MethA, whereas the same do se of IL-2 did not. The in vivo antitumor effect of IL-15 was synergistical ly enhanced by additive administration of IL-12. Combination therapy of IL- 15 and IL-12 protected mice from death from bloody pleural fluid. Such trea tment induced marked increases in the number of CD3(-)IL-2R beta(+) cells c orresponding to natural killer (NK) cells and the production of interferon gamma (IFN gamma) by T cells in the thoracic exudate cells (TEC). Administr ation of anti-IFN gamma mAb partly inhibited the protective effect of a com bination of IL-15 and IL-12. A tumor-neutralizing (Winn) assay revealed tha t the antitumor activity of effector cells in the TEC was abrogated by trea tment with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatme nt with IL-15 in combination with IL-12 may enhance the activities of NK an d CD8(+) T cells in the TEC, providing strong antitumor activity against th e malignant pleurisy. These results suggest that IL-15 together with IL-12 may have potential for the immunotherapy of some types of malignant pleuris y.