IL-1 Contributes to the Anti-Cancer Efficacy of Ingenol Mebutate.
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.
Inflammation Biology, and Cancer Drug Mechanism Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Thuy T
TT
Le
Leo Pharma, Copenhagen, Denmark.
Kresten
K
Skak
Inflammasome Laboratory, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia.
Kate
K
Schroder
Inflammation Biology, and Cancer Drug Mechanism Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Wayne A
WA
Schroder
Inflammation Biology, and Cancer Drug Mechanism Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Glen M
GM
Boyle
Inflammation Biology, and Cancer Drug Mechanism Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Carly J
CJ
Pierce
Inflammation Biology, and Cancer Drug Mechanism Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Andreas
A
Suhrbier
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004224:Diterpenes / Q000627:therapeutic use*; D005260:Female; D017353:Gene Deletion; D007111:Immunity, Cellular / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000276:immunology
C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D004224:Diterpenes; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88