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Neutrophils Are a Key Component of the Antitumor Efficacy of Topical Chemotherapy with Ingenol-3-Angelate¹

Jodie M. Challacombe^2,*, Andreas Suhrbier^2,3,*, Peter G. Parsons^*, Brad Jones^*, Peter Hampson, Dean Kavanagh, G. Ed Rainger, Melanie Morris^*, Janet M. Lord, Thuy T. T. Le^*, Diem Hoang-Le^* and Steven M. Ogbourne^*

^* Queensland Institute of Medical Research, Brisbane, Queensland, Australia; and Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom

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 Foxn1^nu 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Health and Medical Research Council, Australia; the Queensland Cancer Fund; the British Heart Foundation; and the European Commission (LSHB-CT-2004-503467). D.K. was the recipient of a Wellcome Trust Vacation Scholarship.

² J.M.C. and A.S. should be considered equal first authors.

³ Address correspondence and reprint requests to Dr. Andreas Suhrbier, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Queensland 4029, Australia. E-mail address: andreasS{at}qimr.edu.au

⁴ Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; PKC, protein kinase C; MIP, macrophage inflammatory protein.