NLRC4 suppresses melanoma tumor progression independently of inflammasome activation
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
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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Research Article Immunology

NLRC4 suppresses melanoma tumor progression independently of inflammasome activation

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 8

Expression of NLRC4, and not caspase-1, in macrophages regulates B16F10 tumor growth.

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Expression of NLRC4, and not caspase-1, in macrophages regulates B16F10 ...
(A and B) Nlrc4–/– mice were challenged s.c. with 1 × 105 B16F10 cells alone, a mixture of 1 × 105 B16F10 cells and 5 × 104 WT BMDMs, or 1 × 105 B16F10 cells and 5 × 104 Nlrc4–/– BMDMs. Tumor area was measured every 2 to 3 days (A). Tumor mass was determined at 15 days after inoculation (B). Data are representative of 2 experiments with n = 4 mice per group (A) or pooled from 3 independent experiments (n = 12–15 mice per group; B). (C and D) Nlrc4–/– mice were challenged s.c. with 1 × 105 B16F10 cells alone or a mixture of 1 × 105 B16F10 cells and 5 × 104 Casp1–/– BMDMs. Tumor area was measured every 2 to 3 days (C) and tumor mass was determined at 18 days after inoculation (D). Data are representative of 2 experiments each with n = 6 mice per group (C) or pooled from 2 independent experiments (n = 12–13 mice per group; D). (A) Error bars represent SEM. *P ≤ 0.05 and **P ≤ 0.01 (for B16F10 plus WT BMDMs compared with B16F10 plus Nlrc4–/– BMDMs); #P ≤ 0.05 (for B16F10 compared with B16F10 plus WT BMDMs), 2-way ANOVA with Tukey’s HSD post-test for multiple comparisons. (B and D) *P ≤ 0.05, unpaired 2-tailed Student’s t test. (C) Error bars represent SEM. *P ≤ 0.05, 2-way ANOVA with Sidak’s multiple comparisons test.