title: Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors.
abstract: The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U805, Villejuif, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aymeric
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.forename: Carla
authors.initials: C
authors.lastname: Ortiz
authors.forename: Karim
authors.initials: K
authors.lastname: Vermaelen
authors.forename: Theocharis
authors.initials: T
authors.lastname: Panaretakis
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Schlemmer
authors.forename: Ezgi
authors.initials: E
authors.lastname: Tasdemir
authors.forename: Martin
authors.initials: M
authors.lastname: Uhl
authors.forename: Pierre
authors.initials: P
authors.lastname: Génin
authors.forename: Ahmet
authors.initials: A
authors.lastname: Civas
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Jean
authors.initials: J
authors.lastname: Kanellopoulos
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Nicole M
authors.initials: NM
authors.lastname: McLaughlin
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007109:Immunity / Q000276:immunology; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013945:Thymoma / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1