Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors.
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.
Ghiringhelli
François
F
Institut National de la Santé et de la Recherche Médicale, U805, Villejuif, France.
Apetoh
Lionel
L
Tesniere
Antoine
A
Aymeric
Laetitia
L
Ma
Yuting
Y
Ortiz
Carla
C
Vermaelen
Karim
K
Panaretakis
Theocharis
T
Mignot
Grégoire
G
Ullrich
Evelyn
E
Perfettini
Jean-Luc
JL
Schlemmer
Frédéric
F
Tasdemir
Ezgi
E
Uhl
Martin
M
Génin
Pierre
P
Civas
Ahmet
A
Ryffel
Bernhard
B
Kanellopoulos
Jean
J
Tschopp
Jürg
J
André
Fabrice
F
Lidereau
Rosette
R
McLaughlin
Nicole M
NM
Haynes
Nicole M
NM
Smyth
Mark J
MJ
Kroemer
Guido
G
Zitvogel
Laurence
L
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
D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1