Targeting inflammasome/IL-1 pathways for cancer immunotherapy

Sci Rep. 2016 Oct 27;6:36107. doi: 10.1038/srep36107.

Abstract

The inflammatory microenvironment has been shown to play important roles in various stages of tumor development including initiation, growth, and metastasis. The inflammasome is a critical innate immune pathway for the production of active IL-1β, a potent inflammatory cytokine. Although inflammasomes are essential for host defense against pathogens and contribute to autoimmune diseases, their role in tumor progression remains controversial. Here, our results demonstrate that the inflammasome and IL-1β pathway promoted tumor growth and metastasis in animal and human breast cancer models. We found that tumor progression was associated with the activation of inflammasome and elevated levels of IL-1β at primary and metastatic sites. Mice deficient for inflammasome components exhibited significantly reduced tumor growth and lung metastasis. Furthermore, inflammasome activation promoted the infiltration of myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into tumor microenvironments. Importantly, blocking IL-1R with IL-1R antagonist (IL-Ra) inhibited tumor growth and metastasis accompanied by decreased myeloid cell accumulation. Our results suggest that targeting the inflammasome/IL-1 pathway in tumor microenvironments may provide a novel approach for the treatment of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Immunotherapy*
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Myeloid-Derived Suppressor Cells / cytology
  • Myeloid-Derived Suppressor Cells / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Proteins / genetics
  • NLR Proteins / metabolism
  • Receptors, Interleukin-1 / agonists
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction

Substances

  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • Nlrp3 protein, mouse
  • Receptors, Interleukin-1
  • Caspase 1