Journal
NATURE MEDICINE
Volume 15, Issue 10, Pages 1170-U99Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2028
Keywords
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Funding
- Ligue Nationale contre le Cancer
- Fondation pour la Recherche Medicale
- European Union
- association for International cancer research
- Canceropole Ile-de-France
- Institut National du Cancer
- Agence Nationale pour la Recherche
- European Molecular Biology Organization
- National Health
- Association pour la recherche sur le cancer RC
- National Health and Medical Research Council of Australia
- Cancer Council of Victoria
- China Scholarship Council
- Leukemia Foundation
- European Respiratory Society Fellowship [605]
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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.
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