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.
Interleukin (IL)-15 is a pleiotropic cytokine that is important for innate and adaptive immune cell homeostasis. The expression of IL-15 protein is controlled by posttranscriptional mechanisms. Here, we constructed a human IL-15 expression vector consisting of the human IL-2 signal peptide, the human IL-15 mature peptide-coding sequences, and an out-of-frame human growth hormone gene. Human prostate cancer cells, PC-3, transfected with this highly secretable form of the IL-15 gene, successfully secreted abundant bioactive IL-15 protein. In nude mice, the growth of PC-3 cells producing IL-15 was remarkably retarded. NK cell-depletion using anti-asialo GM1 antibody restored tumorigenicity. Histologically, tumors derived from IL-15-producing PC-3 cells contained necrotic areas with high apoptotic index. Splenocytes incubated with supernatant of transfectants killed target PC-3 cells and expressed a significantly high level of mIFN-gamma mRNA. These observations suggest that NK cell-mediated, anti-tumor effects of IL-15 could provide a potential rationale for gene therapy of prostate cancer.
Suzuki
K
K
Department of Urology, Gunma University School of Medicine, Maebashi, Japan. kazu@showa.gunma-u.ac.jp
Nakazato
H
H
Matsui
H
H
Hasumi
M
M
Shibata
Y
Y
Ito
K
K
Fukabori
Y
Y
Kurokawa
K
K
Yamanaka
H
H
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D015316:Genetic Therapy; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017077:Culture Media, Conditioned; D019409:Interleukin-15; D007376:Interleukin-2; D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; D007371:Interferon-gamma