Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors

被引：1538

作者：

Ghiringhelli, Francois ^{[1
,2
,3
,4
]}

Apetoh, Lionel ^{[1
,2
,5
,6
]}

Tesniere, Antoine ^{[2
,5
,7
]}

Aymeric, Laetitia ^{[1
,2
,5
]}

Ma, Yuting ^{[1
,2
,5
]}

Ortiz, Carla ^{[1
,2
,5
,8
]}

Vermaelen, Karim ^{[1
,2
,5
,9
]}

Panaretakis, Theocharis ^{[2
,5
,7
]}

Mignot, Gregoire ^{[1
,2
,3
,4
]}

Ullrich, Evelyn ^{[1
,2
,5
]}

Perfettini, Jean-Luc ^{[2
,5
,7
]}

Schlemmer, Frederic ^{[2
,5
,7
]}

Tasdemir, Ezgi ^{[2
,5
,7
]}

Uhl, Martin ^{[10
]}

Genin, Pierre ^{[11
]}

Civas, Ahmet ^{[11
]}

Ryffel, Bernhard ^{[12
]}

Kanellopoulos, Jean ^{[13
]}

Tschopp, Juerg ^{[14
]}

Andre, Fabrice ^{[1
,2
,5
]}

Lidereau, Rosette ^{[15
]}

McLaughlin, Nicole M. ^{[16
]}

Haynes, Nicole M. ^{[16
]}

Smyth, Mark J. ^{[16
]}

Kroemer, Guido ^{[2
,5
,7
]}

Zitvogel, Laurence ^{[1
,2
,5
,17
]}

机构：

[1] INSERM, U805, Villejuif, France

[2] Inst Gustave Roussy, Villejuif, France

[3] INSERM, AVENIR Team, CRI 866, Dijon, France

[4] Ctr Georges Francois Leclerc, Dijon, France

[5] Univ Paris Sud, Villejuif, France

[6] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA

[7] INSERM, U848, Villejuif, France

[8] Univ Chile, Fac Ciencias Quim Farmaceut, Ctr FONDAP Estudios Mol Celula, Santiago, Chile

[9] Ghent Univ Hosp, Dept Resp Med, Immunoregulat Lab, Ghent, Belgium

[10] Inst Pasteur, INSERM, U818, F-75724 Paris, France

[11] Univ Paris 05, CNRS, Lab Regulat Transcript & Malad Genet, UPR 2228, Paris 06, France

[12] CNRS, Transgenose Inst, IEM, UMR6218, F-45071 Orleans, France

[13] Univ Paris, CNRS, UMR8619, Orsay, France

[14] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland

[15] Ctr Rene Huguenin, INSERM, U735, St Cloud, France

[16] Peter MacCallum Canc Ctr, Canc Immunol Program, Melbourne, Vic, Australia

[17] CICBT507, Villejuif, France

来源：

NATURE MEDICINE | 2009年 / 15卷 / 10期

基金：

英国医学研究理事会;

关键词：

CALRETICULIN EXPOSURE; ALA POLYMORPHISM; P2X(7) RECEPTOR; B-CELLS; INNATE; CANCER; IDENTIFICATION; CASPASE-1; RELEASE; IL-1;

D O I：

10.1038/nm.2028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-1 beta (IL-1 beta). 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-1 beta 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.

引用

页码：1170 / U99

页数：10

共 52 条

[1] Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function [J].