Natural killer cell depletion confounds the antitumor mechanism of endogenous IL-12 overexpression Journal Article


Authors: Miller, G.; Bleier, J. I.; Antonescu, C.; Pillarisetty, V. G.; Shah, A. B.; Lahrs, S.; DeMatteo, R. P.
Article Title: Natural killer cell depletion confounds the antitumor mechanism of endogenous IL-12 overexpression
Abstract: IL-12 gene transfer to hepatocytes using a recombinant adenovirus vector (AdIL-12) has been shown to protect against primary and metastatic liver tumors in mice. However, the mechanism of protection has been elusive and studies using depleting monoclonal antibodies or transgenic mice have purported it to be independent of T and NK cells. We postulated that depletion of NK cells may distort the experimental model and misrepresent the antitumor mechanism by altering the magnitude and duration of transgene expression. We show in mice treated with AdIL-12 that NK depletion increased serum IL-12 levels by more than 250-fold and prolonged transgene expression by nearly 2 weeks compared to nondepleted mice. To determine the contribution of NK cells to tumor protection after AdIL-12 treatment, we analyzed NK cells from treated animals. Isolated NK cells were markedly activated in terms of their lytic activity and IFN-γ secretion. Adoptive transfer of NK cells from mice that had been treated with AdIL-12 to naive mice was sufficient to confer protection against colorectal hepatic metastases. This protection was mediated in part by NK-cell production of IFN-γ. Our findings indicate that NK-cell depletion distorts the model of systemic AdIL-12 administration by markedly altering transgene expression, which then may potentiate other antitumor mechanisms, and that endogenous IL-12 overexpression activates NK cells, rendering them sufficient to protect against liver metastases. These data have critical implications for investigating the immunologic mechanisms of experimental models that utilize gene transfer. © 2004 Wiley-Liss, Inc.
Keywords: controlled study; nonhuman; liver neoplasms; flow cytometry; neoplasms; colorectal cancer; cd8-positive t-lymphocytes; t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; gene overexpression; animal experiment; animal model; antineoplastic activity; mice, inbred balb c; time factors; gene transfer; transgenic mouse; viral gene delivery system; genetic vectors; colorectal neoplasms; liver metastasis; cytokines; gamma interferon; cd4-positive t-lymphocytes; cell isolation; neoplasm metastasis; transgene; long term care; natural killer cell; adoptive transfer; killer cells, natural; tumor immunity; cytokine production; cytotoxicity, immunologic; adenovirus vector; peritoneum metastasis; cell activation; cell protection; cell separation; interleukin 12; transgenes; t lymphocytes; spleen cell; gene transfer techniques; experimental model; liver protection; interleukin-12; nk cells; interferon type ii; male; priority journal; article
Journal Title: International Journal of Cancer
Volume: 110
Issue: 3
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 2004-06-20
Start Page: 395
End Page: 402
Language: English
DOI: 10.1002/ijc.20131
PROVIDER: scopus
PUBMED: 15095305
DOI/URL:
Notes: Int. J. Cancer -- Cited By (since 1996):5 -- Export Date: 16 June 2014 -- CODEN: IJCNA -- Source: Scopus
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Citation Impact
MSK Authors
  1. George Miller
    18 Miller
  2. Ronald P DeMatteo
    635 DeMatteo
  3. Cristina R Antonescu
    764 Antonescu
  4. Joshua Israel Bleier
    13 Bleier
  5. Alaap Shah
    20 Shah
  6. Svenja   Lahrs
    9 Lahrs