Ghiringhelli François, Apetoh Lionel, Tesniere Antoine, Aymeric Laetitia, Ma Yuting, Ortiz Carla, Vermaelen Karim, Panaretakis Theocharis, Mignot Grégoire, Ullrich Evelyn, Perfettini Jean-Luc, Schlemmer Frédéric, Tasdemir Ezgi, Uhl Martin, Génin Pierre, Civas Ahmet, Ryffel Bernhard, Kanellopoulos Jean, Tschopp Jürg, André Fabrice, Lidereau Rosette, McLaughlin Nicole M, Haynes Nicole M, Smyth Mark J, Kroemer Guido, Zitvogel Laurence
Institut National de la Santé et de la Recherche Médicale, U805, Villejuif, France.
Nat Med. 2009 Oct;15(10):1170-8. doi: 10.1038/nm.2028. Epub 2009 Sep 20.
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.
抗癌化疗的疗效可能取决于树突状细胞（DCs），DCs可呈递来自垂死癌细胞的抗原，以启动产生肿瘤特异性干扰素-γ（IFN-γ）的T淋巴细胞。我们在此表明，垂死的肿瘤细胞会释放ATP，ATP随后作用于DCs的P2X（7）嘌呤能受体，并触发NOD样受体家族含pyrin结构域3蛋白（NLRP3）依赖性半胱天冬酶-1激活复合物（“炎性小体”），从而促使白细胞介素-1β（IL-1β）分泌。在缺乏功能性IL-1受体1的情况下，以及在Nlpr3缺陷（Nlrp3（-/-））或半胱天冬酶-1缺陷（Casp-1（-/-））的小鼠中，垂死肿瘤细胞对产生IFN-γ的CD8 + T细胞的启动作用失败，除非提供外源性IL-1β。因此，事实证明抗癌化疗对在嘌呤能受体P2rx7（-/-）、Nlrp3（-/-）或Casp1（-/-）宿主中形成的肿瘤无效。携带P2RX7功能缺失等位基因的蒽环类药物治疗的乳腺癌患者比携带正常等位基因的患者更快发生转移性疾病。这些结果表明，NLRP3炎性小体将针对垂死肿瘤细胞的先天性和适应性免疫反应联系起来。
