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NLRP3

Nucleotide-binding oligomerization domain-like receptor family, pyrin domain- containing 3 (NLRP3) is involved in the assembly of the NLRP3 inflammasome, leading to enhanced antitumor response.

Expression and normal function

NLRP3 is a protein expressed in antigen-presenting cells (APCs) such as dendritic cells (DCs), monocytes, and macrophages¹
NLRP3 is involved in the assembly of the NLRP3 inflammasome, a key mediator of innate immunity and priming of T cells^2,3

NLRP3 expression is first induced by inflammatory signals⁴

Specifically, NLRP3 expression and activation requires 2 separate inflammatory signals. Full activation of the inflammasome may be restricted to sites of inflammation, potentially avoiding damage to healthy cells^5,6

Factors released during tumor cell death, such as adenosine triphosphate (ATP), trigger assembly of the NLRP3 inflammasome, which then converts inactive IL-1β and IL-18 into their mature, active forms^3,7,8
These cytokines initiate APC priming as well as NK- and cytotoxic T-cell activation, leading to increased recruitment and antitumor function of these primary effector cells^2,3,9-12

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Preclinical evidence

Preclinical studies suggest that the NLRP3 agonists can activate NK cells and initiate the priming of T cells, which promotes tumor inflammation and enhances antitumor function^2,3,13

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REFERENCES–NLRP3

1. Guarda G, Zenger M, Yazdi AS, et al. Differential expression of NLRP3 among hematopoietic cells. J Immunol. 2011;186(4):2529-2534. 2. Dupaul-Chicoine J, Arabzadeh A, Dagenais M, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity. 2015;43(4):751-763. 3. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170-1178. 4. Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262. doi:10.3389/fphar.2015.00262. 5. Embry CA, Franchi L, Nuñez G, Mitchell TC. Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci Signal. 2011;4(171):ra28. doi:10.1126/scisignal.2001486. 6. Sharma D, Kanneganti T-D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J Cell Biol. 2016;213(6):617-629. 7. Chow MT, Möller A, Smyth MJ. Inflammation and immune surveillance in cancer. Semin Cancer Biol. 2012;22(1):23-32. 8. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021. 9. Ben-Sasson SZ, Hogg A, Hu-Li J, et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med. 2013;210(3):491-502. 10. Maltez VI, Tubbs AL, Cook KD, et al. Inflammasomes coordinate pyroptosis and natural killer cell cytotoxicity to clear infection by a ubiquitous environmental bacterium. Immunity. 2015;43(5):987-997. 11. Freeman BE, Hammarlund E, Raué H-P, Slifka MK. Regulation of innate CD8+ T-cell activation mediated by cytokines. Proc Natl Acad Sci U S A. 2012;109(25):9971-9976. 12. Cooper MA, Fehniger TA, Ponnappan A, Mehta V, Wewers MD, Caligiuri MA. Interleukin-1β costimulates interferon-γ production by human natural killer cells. Eur J Immunol. 2001;31(3):792-801. 13. Chow MT, Sceneay J, Paget C, et al. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 2012;72(22):5721-5732.