Editors' ChoiceCancer

Inflammasome activation to protect against colorectal cancer metastasis?

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Science Translational Medicine  18 Nov 2015:
Vol. 7, Issue 314, pp. 314ec196
DOI: 10.1126/scitranslmed.aad5907

Currently, innate immunity is in the limelight for potential contributions to the immune response against cancer. Natural killer (NK) cells are a critical component of this innate immune response, as they can directly kill tumor cells; however, tumors often develop inhibitory mechanisms to escape attack by these cells. Approaches that maintain activation of NK cells in the context of these escape mechanisms could lead to improved immunotherapeutics.

Recent work by Dupaul-Chicoine et al. highlights a promising mechanism by which NK cell activation is maintained through NLRP3 inflammasome activation. The authors set off to examine the impact of inflammasome activation in colorectal cancer metastasis in the liver, a site exposed to intestinal bacteria through the portal vein that also expresses pattern recognition receptors that activate the inflammasome. The authors first noted that caspase-1, which requires the inflammasome for activity, when knocked down, enhanced colorectal cancer liver metastasis growth in a mouse model. They went on to show in mice deficient for Nlrp3 that Nlrp3 was required for suppression of colorectal cancer metastasis, whereas other inflammasome proteins were not. IL-18, but not IL-1, supported the suppression of liver metastasis, and IL-18 could mediate this effect in the absence of the adaptive immune system. In these models, the inflammasome suppressed metastatic growth through NK cell–induced tumor cell death.

The creative approach and results of this study leave an impression that not only has the innate immune system been overlooked in the quest to activate antitumor immunity, but also that there are likely more unexpected innate targets out there waiting to be discovered to activate antitumor immunity. The next step may be investigating inflammasome activity in human colorectal cancers in association with patient metastasis to support these intricate mouse studies.

J. Dupaul-Chicoine et al., The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43, 751–763 (2015). [Abstract]

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