The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity

Immunity. 2015 Oct 20;43(4):751-63. doi: 10.1016/j.immuni.2015.08.013. Epub 2015 Sep 15.


The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.

Keywords: Fas; NLRP3; caspase-1; cell death; colorectal cancer; immunosurveillance; inflammasome; innate immunity; interleukin-18; metastasis; natural killer (NK) cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / secondary*
  • Animals
  • Apoptosis Regulatory Proteins / deficiency
  • Calcium-Binding Proteins / deficiency
  • Carrier Proteins / physiology*
  • Caspase 1 / deficiency
  • Cell Line, Tumor
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology*
  • Cytotoxicity, Immunologic
  • DNA-Binding Proteins / deficiency
  • Fas Ligand Protein / physiology
  • Gastrointestinal Microbiome
  • Immunity, Innate
  • Immunologic Surveillance
  • Inflammasomes / deficiency
  • Inflammasomes / physiology*
  • Interleukin-18 / physiology
  • Interleukin-1beta / physiology
  • Killer Cells, Natural / immunology*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / physiology
  • Radiation Chimera
  • Radiation Tolerance
  • Tumor Microenvironment


  • Aim2 protein, mouse
  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Fas Ligand Protein
  • Fasl protein, mouse
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Ipaf protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Proteins
  • Nlrp3 protein, mouse
  • Caspase 1