Abstract
Ingenol mebutate is approved for the topical treatment of actinic keratoses and may ultimately also find utility in treating skin cancers. Here we show that relapse rates of subcutaneous B16 melanoma tumours treated topically with ingenol mebutate were not significantly different in C57BL/6 and Rag1-/- mice, suggesting B and T cells do not play a major role in the anti-cancer efficacy of ingenol mebutate. Relapse rates were, however, significantly increased in MyD88-/- mice and in C57BL/6 mice treated with the anti-IL-1 agent, anakinra. Ingenol mebutate treatment induces a pronounced infiltration of neutrophils, which have been shown to have anti-cancer activity in mice. Herein we provide evidence that IL-1 promotes neutrophil recruitment to the tumour, decreases apoptosis of infiltrating neutrophils and increases neutrophil tumour killing activity. These studies suggest IL-1, via its action on neutrophils, promotes the anti-cancer efficacy of ingenol mebutate, with ingenol mebutate treatment causing both IL-1β induction and IL-1α released from keratinocytes.
Highlights
Ingenol mebutate (Picato1) is an approved topical drug for field treatment of actinic keratoses (AKs) [1,2,3]
Experiments using the LK2 squamous cell carcinoma line grown in Foxn1nu mice suggesting a role for antibodies and antibody dependent cellular cytotoxicity (ADCC) in preventing relapse [21]
Relapse rates were not significantly different between Rag1-/- and C57BL/6 mice (Figure A in S1 File), suggesting neither B nor T cells play a major role in the anti-tumour efficiency of ingenol mebutate in the B16 model
Summary
Ingenol mebutate (Picato1) is an approved topical drug for field treatment of actinic keratoses (AKs) [1,2,3]. In about 8% of cases, AKs can progress to invasive squamous cell carcinomas (SCCs) [5], the second most common form of skin cancer. Removal of AKs and mutated keratinocytes by ingenol mebutate treatment seeks to reduce the subsequent risk of developing SCCs [1,6,7,8]. Ingenol mebutate may find utility in treating other skin cancers [9,10], with efficacy shown in human studies for SCCs and basal cell carcinomas [11,12,13]. In vivo topical drug application induces primary necrosis of (i) keratinocytes, including patches of keratinocytes bearing p53 mutations and (ii) subcutaneous tumours cells growing beneath the treatment site [16,17]. Topical treatment in humans [7,18,19] and mice [16] results in a rapid onset transient
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