title: The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells.
abstract: The inflammasome is a proteolysis complex that generates the active forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18. Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3(-/-) mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended on CD8(+) T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3(-/-) hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3(-/-) MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti-Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3(-/-) mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.
authors.affiliation: Department of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7295, USA.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: van Deventer
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Burgents
authors.forename: Qing Ping
authors.initials: QP
authors.lastname: Wu
authors.forename: Rita-Marie T
authors.initials: RM
authors.lastname: Woodford
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Erin
authors.initials: E
authors.lastname: McElvania-Tekippe
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000276:immunology / Q000628:therapy; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse