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-alpha, and IL-1beta, 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.