Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism.

ABSTRACT

Interleukin 15 (IL-15) is a novel cytokine that shares no homology with IL-2, but it requires the use of beta and gamma chains of the IL-2 receptor complex for binding and signaling. In vitro studies have shown induction of CTL and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMCs) from normal donors by IL-15 against known tumor targets. The present study attempts to define the role of IL-15 in generating LAK activity from melanoma patient lymphocytes. PBMCs of patients newly diagnosed with metastatic melanoma were incubated with different doses of recombinant human IL-15 and tested against autologous tumor cells, LAK sensitive cell lines (i.e., FMEX and Daudi), as well as the natural killer-sensitive cell line K562, in a 15-h 51Cr release assay. The effect of IL-15 was found to be both time and dose dependent, with peak activity detected after 2 or 3 days of culture with 100 ng/ml of this cytokine. LAK and not CTL activity in patient PBMCs was detected by the inability of mAbs against CD4, CD8, and MHC class I to effectively block lysis of autologous tumor and FMEX melanoma cells. In addition, interaction via the CD18 adhesion molecule was shown to be critical in IL-15-induced LAK-mediated lysis of autologous tumor cells. Finally, incubation of patient PBMCs with IL-15 for 6 h resulted in the up-regulation of perforin mRNA transcription. These findings suggest that LAK activity can be generated from melanoma patient PBMCs in the presence of IL-15 to lyse autologous tumor cells in a non-MHC-restricted manner. This new cytokine may play an important role in antitumor immunity with a possible use for cancer immunotherapy.