Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism.
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.
Gamero
A M
AM
Department of Biochemistry, University of South Florida, College of Medicine, Tampa, USA.
Ussery
D
D
Reintgen
D S
DS
Puleo
C A
CA
Djeu
J Y
JY
D001706:Biopsy; D018821:CD18 Antigens / Q000502:physiology*; D006801:Humans; D007167:Immunotherapy; D019409:Interleukin-15; D007378:Interleukins / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D012680:Sensitivity and Specificity; D013268:Stimulation, Chemical; D014158:Transcription, Genetic
D018821:CD18 Antigens; D019409:Interleukin-15; D007378:Interleukins; D008562:Membrane Glycoproteins