Journal article
Neutrophils Are a Key Component of the Antitumor Efficacy of Topical Chemotherapy with Ingenol-3-Angelate
Journal of Immunology, Vol.177(11), pp.8123-8132
2006
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-1, 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 tumoricidal-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 neutrophils can be induced to mediate important anticancer activity with specific chemotherapeutic agents.
Details
- Title
- Neutrophils Are a Key Component of the Antitumor Efficacy of Topical Chemotherapy with Ingenol-3-Angelate
- Authors
- J M Challacombe (Author) - Queensland Institute of Medical ResearchA Suhrbier (Author) - Queensland Institute of Medical ResearchP Parsons (Author) - Queensland Institute of Medical ResearchB Jones (Author) - Queensland Institute of Medical ResearchP Hampson (Author) - University of BirminghamD Kavanagh (Author) - University of BirminghamG E Rainger (Author) - University of BirminghamM Morris (Author) - Queensland Institute of Medical ResearchJ Lord (Author) - University of BirminghamThuy T T Le (Author) - Queensland Institute of Medical ResearchD Hoang-Le (Author) - Queensland Institute of Medical ResearchSteven Ogbourne (Author) - Queensland Institute of Medical Research
- Publication details
- Journal of Immunology, Vol.177(11), pp.8123-8132
- Publisher
- American Association of Immunologists
- Date published
- 2006
- DOI
- 10.4049/jimmunol.177.11.8123
- ISSN
- 0022-1767
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99449443102621
- Output Type
- Journal article
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- Immunology
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