IL-1 Contributes to the Anti-Cancer Efficacy of Ingenol Mebutate

PLoS One. 2016 Apr 21;11(4):e0153975. doi: 10.1371/journal.pone.0153975. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Diterpenes / therapeutic use*
  • Female
  • Gene Deletion
  • Immunity, Cellular / drug effects
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-1 / immunology*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / immunology
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / genetics
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / immunology


  • 3-ingenyl angelate
  • Antineoplastic Agents
  • Diterpenes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88

Grants and funding

The research was primarily conducted at QIMR Berghofer Medical Research Institute and was largely funded by Leo Pharma, and in part by a grant from the Australian National Health & Medical Research Council (APP1043104). Leo provided support in the form of salaries for TTL and consumables, was involved in the initial study design, but was not involved in data collection and analysis. Leo was involved in the decision to publish, but provided minimal input into the writing of the manuscript. K. Schroder is supported by an Australian Research Council Future Fellowship (FT130100361), and the Queensland Smart Futures Fund. AS is a Principal Research Fellow with the National Health & Medical Research Council, Australia (APP1058391).