Immunity 2015 Oct 15;43(4):751-63. Epub 2015 Sep 15.
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:
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.