NK cell-mediated anti-tumor immune response to human prostate cancer cell, PC-3: immunogene therapy using a highly secretable form of interleukin-15 gene transfer

Abstract

Interleukin (IL)-15 is a pleiotropic cytokine that is important forinnate and adaptive immune cell homeostasis. The expression of IL-15protein is controlled by posttranscriptional mechanisms. Here, weconstructed a human IL-15 expression vector consisting of the humanIL-2 signal peptide, the human IL-15 mature peptide-coding sequences,and an out-of-frame human growth hormone gene. Human prostate cancercells, PC-3, transfected with this highly secretable form of the IL-15gene, successfully secreted abundant bioactive IL-15 protein. In nudemice, the growth of PC-3 cells producing IL-15 was remarkably retarded.NK cell-depletion using anti-asialo GM1 antibody restoredtumorigenicity. Histologically, tumors derived from IL-15-producingPC-3 cells contained necrotic areas with high apoptotic index.Splenocytes incubated with supernatant of transfectants killed targetPC-3 cells and expressed a significantly high level of mIFN-γ mRNA.These observations suggest that NK cell-mediated, anti-tumor effects ofIL-15 could provide a potential rationale for gene therapy of prostatecancer.