NLRC4 suppresses melanoma tumor progression independently of inflammasome activation.
Members of the NLR family can assemble inflammasome complexes with the adaptor protein ASC and caspase-1 that result in the activation of caspase-1 and the release of IL-1β and IL-18. Although the NLRC4 inflammasome is known to have a protective role in tumorigenesis, there is an increased appreciation for the inflammasome-independent actions of NLRC4. Here, we utilized a syngeneic subcutaneous murine model of B16F10 melanoma to explore the role of NLRC4 in tumor suppression. We found that NLRC4-deficient mice exhibited enhanced tumor growth that was independent of the inflammasome components ASC and caspase-1. Nlrc4 expression was critical for cytokine and chemokine production in tumor-associated macrophages and was necessary for the generation of protective IFN-γ-producing CD4+ and CD8+ T cells. Tumor progression was diminished when WT or caspase-1-deficient, but not NLRC4-deficient, macrophages were coinjected with B16F10 tumor cells in NLRC4-deficient mice. Finally, examination of human primary melanomas revealed the extensive presence of NLRC4+ tumor-associated macrophages. In contrast, there was a paucity of NLRC4+ tumor-associated macrophages observed in human metastatic melanoma, supporting the concept that NLRC4 expression controls tumor growth. These results reveal a critical role for NLRC4 in suppressing tumor growth in an inflammasome-independent manner.
Ann M
AM
Janowski
Oscar R
OR
Colegio
Emma E
EE
Hornick
Jennifer M
JM
McNiff
Matthew D
MD
Martin
Vladimir P
VP
Badovinac
Lyse A
LA
Norian
Weizhou
W
Zhang
Suzanne L
SL
Cassel
Fayyaz S
FS
Sutterwala
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D018925:Chemokines; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020170:Caspase 1