Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate

Challacombe, Jodie M., Suhrbier, Andreas, Parsons, Peter G., Jones, Brad, Hampson, Peter, Kavanagh, Dean, Rainger, G. Ed, Morris, Melanie, Lord, Janet M., Le, Thuy T. T., Diem, Hoang-Le and Ogbourne, Steven M. (2006) Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. Journal of Immunology, 177 11: 8123-8132.

Author Challacombe, Jodie M.
Suhrbier, Andreas
Parsons, Peter G.
Jones, Brad
Hampson, Peter
Kavanagh, Dean
Rainger, G. Ed
Morris, Melanie
Lord, Janet M.
Le, Thuy T. T.
Diem, Hoang-Le
Ogbourne, Steven M.
Title Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2006-12-01
Sub-type Article (original research)
Open Access Status Not yet assessed
Volume 177
Issue 11
Start page 8123
End page 8132
Total pages 10
Place of publication Bethesda, MD,United States
Publisher American Association of Immunologists
Language eng
Formatted abstract
Harnessing neutrophils for the eradication of cancer cells remains an attractive but still controversial notion. In this study, we provide evidence that neutrophils are required to prevent relapse of skin tumors following topical treatment with a new anticancer agent, ingenol-3-angelate (PEP005). Topical PEP005 treatment induces primary necrosis of tumor cells, potently activates protein kinase C, and was associated with an acute T cell-independent inflammatory response characterized by a pronounced neutrophil infiltrate. In Foxn1nu mice depleted of neutrophils and in CD18-deficient mice (in which neutrophil extravasation is severely impaired) PEP005 treatment was associated with a >70% increase in tumor relapse rates. NK cell or monocyte/macrophage deficiency had no effect on relapse rates. Both in vitro and in mice, PEP005 induced MIP-2/IL-8, TNF-α, and IL-1β, all mediators of neutrophil recruitment and activation. In vitro, PEP005 activated human endothelial cells resulting in neutrophil adhesion and also induced human neutrophils to generate tamoricidal-reactive oxygen intermediates. Treatment of tumors with PEP005 significantly elevated the level of anticancer Abs, which were able to promote neutrophil-mediated Ab-dependent cellular cytotoxicity (ADCC) in vitro. PEP005 treatment of tumors grown in SCID mice was also associated with >70% increase in tumor relapse rates. Taken together, these data suggest a central role for neutrophil-mediated ADCC in preventing relapse. PEP005-mediated cure of tumors therefore appears to involve initial chemoablation followed by a neutrophil-dependent ADCC-mediated eradication of residual disease, illustrating that neatrophils can be induced to mediate important anticancer activity with specific chemotherapeutic agents.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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