Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors
Open accessAbstract
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.
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Six DAMPs have been mechanistically linked to perception of RCD as immunogenic: CALR, ATP, HMGB1, type I IFN, cancer cell-derived nucleic acids, and ANXA1.
“So far, six DAMPs have been mechanistically linked to the perception of RCD as immunogenic: (1) calreticulin (CALR) [865, 866], (2) ATP [867–869], (3) high-mobility group box 1 (HMGB1) [870–872], (4) type I IFN [854, 873, 874], (5) cancer cell-derived nucleic acids [864, 875], and (6) annexin A1 (ANXA1) [876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [869]
RCD is a primary etiological determinant in diseases with irreversible loss of post-mitotic tissues such as myocardial infarction and neurodegeneration.
“On the one hand, RCD constitutes a primary etiological determinant in diseases associated with the irreversible loss of post-mitotic tissues (e.g., myocardial infarction, neurodegeneration) [687, 752, 851, 869, 1035, 1036].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [869]
A loss-of-function P2RX7 allele was associated with poorer prognosis (decreased metastasis-free survival) in early-stage breast cancer patients treated with chemotherapy.
“Consistently, a loss-of-function P2RX7 allele was also associated with poorer prognosis (decreased metastasis-free survival) in early-stage breast cancer patients treated with chemotherapy112.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
The ability of dendritic cells to prime tumour-specific T cells required NLRP3 and P2RX7.
“Dying tumour cells release ATP and, indeed, the ability of dendritic cells to prime tumour-specific T cells required NLRP3 and P2RX7 (REF. 112).”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
Inflammatory responses are important for mounting an effective antitumour response against chemotherapy-induced, immunogenic tumour cell death.
“However, inflammatory responses are equally important for mounting an effective antitumour response against chemotherapy-induced, immunogenic tumour cell death.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
NLRP3-mediated IL-1β production through the ATP-P2RX7 pathway is important for immune surveillance against tumours.
“Furthermore, chemotherapy-treated tumour cells injected into wild-type mice inhibited tumour development when the mice were rechallenged with tumour cells, but this effect was abrogated in NLRP3-deficient and P2RX7-deficient mice112, suggesting that NLRP3-mediated IL-1β production through the ATP–P2RX7 pathway is important for immune surveillance against tumours.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
Dying tumour cells release ATP.
“Dying tumour cells release ATP and, indeed, the ability of dendritic cells to prime tumour-specific T cells required NLRP3 and P2RX7 (REF. 112).”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
Chemotherapy-treated tumour cells injected into wild-type mice inhibited tumour development when the mice were rechallenged with tumour cells, but this effect was abrogated in NLRP3-deficient and P2RX7-deficient mice.
“Furthermore, chemotherapy-treated tumour cells injected into wild-type mice inhibited tumour development when the mice were rechallenged with tumour cells, but this effect was abrogated in NLRP3-deficient and P2RX7-deficient mice112, suggesting that NLRP3-mediated IL-1β production through the ATP–P2RX7 pathway is important for immune surveillance against tumours.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [112]
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- Authors
- Ghiringhelli, F., Apetoh, L., Tesniere, A., Aymeric, L., Ma, Y., Ortiz, C., Vermaelen, K., Panaretakis, T., Mignot, G., Ullrich, E., Perfettini, J.-L., Schlemmer, F., Tasdemir, E., Uhl, M., Génin, P., Civas, A., Ryffel, B., Kanellopoulos, J., Tschopp, J., André, F., Lidereau, R., McLaughlin, N. M., Haynes, N. M., Smyth, M. J., Kroemer, G., & Zitvogel, L.
- Affiliations
- Inserm (FR)
- Université Paris-Sud (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Lausanne (CH)
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Kroemer, Guido
- Zitvogel, Laurence
- ORCID
- Venue
- Nature Medicine
- Published
- 2009-09-20
- Volume
- 15
- Issue
- 10
- Pages
- 1170-1178
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2130153302
- Cited by
- 1,898
- References
- 53
- Citations by year
- 2026: 83 · 2025: 92 · 2024: 114 · 2023: 147 · 2022: 136 · 2021: 166 · 2020: 145 · 2019: 107 · 2018: 89 · 2017: 114 · 2016: 94 · 2015: 98 · 2014: 87 · 2013: 127 · 2012: 113
- FWCI
- 39.82
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- IRIS (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- NLRP3 inflammasome, dendritic cells, IL-1β, caspase-1, cancer cell death, ATP release, IL-1 receptor 1, anthracycline chemotherapy, breast cancer, metastasis, innate-adaptive immune crosstalk
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Dendritic Cells, Immunity, Immunity, Innate, Inflammation, Thymoma, Mice, Knockout, Caspase 1, Mice, Interleukin-1beta
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