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NLRC4 suppresses melanoma tumor progression independently of inflammasome activation
Ann M. Janowski, … , Suzanne L. Cassel, Fayyaz S. Sutterwala
Ann M. Janowski, … , Suzanne L. Cassel, Fayyaz S. Sutterwala
Published September 12, 2016
Citation Information: J Clin Invest. 2016;126(10):3917-3928. https://doi.org/10.1172/JCI86953.
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Research Article Immunology Article has an altmetric score of 2

NLRC4 suppresses melanoma tumor progression independently of inflammasome activation

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Abstract

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.

Authors

Ann M. Janowski, Oscar R. Colegio, Emma E. Hornick, Jennifer M. McNiff, Matthew D. Martin, Vladimir P. Badovinac, Lyse A. Norian, Weizhou Zhang, Suzanne L. Cassel, Fayyaz S. Sutterwala

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Figure 4

Expression of Nlrc4 in hematopoietic cells is important for controlling tumor growth.

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Expression of Nlrc4 in hematopoietic cells is important for controlling ...
(A) Expression of Nlrc4 in BMDMs, fibroblasts, CD4+ T cells, CD8+ T cells, B16F10, and LLC cells was determined by qPCR and represented as expression relative to Nlrc4 expression in BMDMs. Data are representative of 2 independent experiments. (B and C) WT and Nlrc4–/– mice were lethally irradiated and reconstituted with either WT or Nlrc4–/– BM (donor BM → recipient mouse). Mice were injected s.c. with 1 × 105 B16F10 cells. (B) Tumor area was measured every 2 to 3 days. (C) Tumor mass was determined at day 19 after inoculation. (B and C) Data are representative of 2 experiments with n ≥ 9 mice per experiment. (B) Error bars represent SEM. ##P ≤ 0.01 (for Nlrc4–/– → WT compared with WT → WT); ***P ≤ 0.001 and ****P ≤ 0.0001 (for Nlrc4–/– → Nlrc4–/– compared with WT → WT), 2-way ANOVA with Tukey’s HSD post-test for multiple comparisons. (C) *P ≤ 0.05, **P ≤ 0.01, unpaired 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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