title: Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate.
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 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.
authors.affiliation: Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Jodie M
authors.initials: JM
authors.lastname: Challacombe
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
authors.forename: Peter G
authors.initials: PG
authors.lastname: Parsons
authors.forename: Brad
authors.initials: B
authors.lastname: Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Dean
authors.initials: D
authors.lastname: Kavanagh
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
authors.forename: Melanie
authors.initials: M
authors.lastname: Morris
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
authors.forename: Thuy T T
authors.initials: TT
authors.lastname: Le
authors.forename: Diem
authors.initials: D
authors.lastname: Hoang-Le
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ogbourne
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage* / Q000276:immunology; D004952:Esters / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D051379:Mice; D009336:Necrosis; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D016207:Cytokines; D004224:Diterpenes; D004952:Esters; D011493:Protein Kinase C