title: The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.
abstract: 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.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Dupaul-Chicoine
authors.affiliation: The Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Arabzadeh
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: Maryse
authors.initials: M
authors.lastname: Dagenais
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Todd
authors.initials: T
authors.lastname: Douglas
authors.affiliation: Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Champagne
authors.affiliation: Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.affiliation: Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada.
authors.forename: Ian Gaël
authors.initials: IG
authors.lastname: Rodrigue-Gervais
authors.affiliation: The Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Breton
authors.affiliation: Department of Immunology, Center for Integrated Immunology and Vaccine Research, UConn Health, Farmington, CT 06030, USA.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Colpitts
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; The Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; The Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada. Electronic address: maya.saleh@mcgill.ca.
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D002135:Calcium-Binding Proteins / Q000172:deficiency; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000172:deficiency; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology*; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000172:deficiency; D053222:Fas Ligand Protein / Q000502:physiology; D000069196:Gastrointestinal Microbiome; D007113:Immunity, Innate; D007157:Immunologic Surveillance; D058847:Inflammasomes / Q000172:deficiency / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology; D011828:Radiation Chimera; D011836:Radiation Tolerance; D059016:Tumor Microenvironment
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins; C492716:Nlrp3 protein, mouse; D020170:Caspase 1
keywords: Fas; NLRP3; caspase-1; cell death; colorectal cancer; immunosurveillance; inflammasome; innate immunity; interleukin-18; metastasis; natural killer (NK) cells