Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells

Previous studies have demonstrated that IL-15 administration after cyclopho sphamide (CY) injection of C57BL/6J mice bearing the i.m. 76-9 rhabdomyosar coma resulted in a significant prolongation of life. In the present study, we investigated the immune response against the 76-9 experimental lung meta stases after CY + IL-15 therapy. Administration of CY + IL-15, but not IL-1 5 alone, induced prolongation of life and cures in 32% of mice bearing esta blished experimental pulmonary metastases of 76-9 tumor. The CY + IL-15 the rapy resulted in increased levels of NK1.1(+)/LGL-1(+) cells, and CD8(+)/CD 44(+) T cells in PBL, In vitro cytotoxic assay of PBL indicated the inducti on of lymphokine-activated killer cell activity, but no evident tumor-speci fic class I-restricted lytic activity. Survival studies showed that the pre sence of NK and T lymphocytes is necessary for successful CY + IL-15 therap y. Experiments using knockout mice implied that either alpha beta or gamma delta T cells were required for an antitumor effect induced by CY + IL-15 t herapy. However, mice lacking in both alpha beta and gamma delta T cells fa iled to respond to combination therapy. Cured B6 and alpha beta or gamma de lta T cell-deficient mice were immune to rechallenge with 76-9, but not B16 LM tumor. B cell-deficient mice showed a significant improvement in the sur vival rate both after CY and combination CY + IL-15 therapy compared with n ormal B6 mice. Overall, the data suggest that the interaction of NK cells w ith tumor-specific alpha beta or gamma delta T lymphocytes is necessary for successful therapy, while B cells appear to suppress the antitumor effects of CY + IL-15 therapy.