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首页 » 癌症研究 » Nature:科学家揭示程序性坏死如何影响肿瘤微环境促进胰腺癌

Nature:科学家揭示程序性坏死如何影响肿瘤微环境促进胰腺癌

来源:生物谷 2016-04-09 12:47

                              

2016年4月9日讯 /生物谷BIOON/ --近日,来自美国纽约大学医学院的研究人员在国际学术期刊Nature上发表了一项最新研究进展,该研究或将推动胰腺癌免疫治疗方法的开发。

之前认为癌化的胰腺上皮细胞通过caspase8依赖性细胞凋亡发生死亡,而化疗药物也被认为是通过促进肿瘤发生凋亡来发挥杀伤作用。而与此相反,有研究发现癌细胞经常扰乱细胞凋亡过程维持自身存活。除了细胞凋亡还有另外一种程序性细胞死亡——程序性坏死,但目前对于这一过程在胰腺导管腺癌(PDA)中的作用仍不明了。

在这项最新研究中,研究人员报道称组成坏死体(necrosome)的主要成分RIP1和RIP3在PDA 中存在高表达,并且会在化疗药物吉西他滨的作用下进一步上调。在体外阻断necrosome能够促进癌细胞增殖,并诱导形成侵袭性癌症表型。与之相比,在小鼠体内删除RIP3或抑制RIP1反而会延缓癌症进展,同时还会出现免疫原性髓样细胞和T细胞的高度浸润。

该研究发现与RIP1/RIP3信号相关的免疫抑制性肿瘤微环境会部分依赖程序性坏死诱导的趋化因子CXCL1 的表达,阻断CXCL1能够帮助对抗PDA。此外,细胞质内的SAP130(一种组蛋白去乙酰化酶复合体的亚基)以一种RIP1/RIP3依赖性的方式在PDA中表达,它的同源受体——Mincle在肿瘤浸润的髓样细胞中表达上调。当坏死细胞释放出来的SAP130与Mincle发生结合就会促进癌症发生,而删除Mincle则可以阻断癌症发生,这在表型上类似于RIP3删除诱导形成的免疫原性肿瘤微环境。

细胞学研究表明,虽然免疫抑制性巨噬细胞能够促进PDA肿瘤发生,但是一旦删除RIP3或者Mincle,它们就会失去免疫抑制作用。与此同时,RIP3或者Mincle的缺失还会促使T 细胞发生基因重编程,变成抗肿瘤免疫中必不可少的介导成分。

这项研究详细描述了程序性坏死诱导的CXCL1和Mincle信号网络,并发现这两条信号途径能够促进巨噬细胞诱导的适应性免疫抑制,进而促进PDA进展。了解这些信息对于开展胰腺导管腺癌的免疫治疗具有重要意义。(生物谷Bioon.com)

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doi:10.1038/nature17403 

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

Lena Seifert, Gregor Werba, Shaun Tiwari, Nancy Ngoc Giao Ly, Sara Alothman, Dalia Alqunaibit, Antonina Avanzi, Rocky Barilla, Donnele Daley, Stephanie H. Greco, Alejandro Torres-Hernandez, Matthew Pergamo, Atsuo Ochi, Constantinos P. Zambirinis, Mridul Pansari, Mauricio Rendon, Daniel Tippens, Mautin Hundeyin, Vishnu R. Mani, Cristina Hajdu, Dannielle Engle & George Miller

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis1. Conversely, cancer cells often disrupt apoptosis to survive2, 3. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs4, 5. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle—its cognate receptor—was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

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