通过CXCL1和Mincle诱导的免疫抑制促进胰腺瘤发生
Lena Seifert1, Gregor Werba1, Shaun Tiwari1
1S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Nature
|April 7, 2016
概括
一种涉及RIP1和RIP3的编程细胞死亡途径,通过抑制免疫微环境促进胰腺癌的进展. 抑制亡或其信号通路可以增强抗瘤免疫力,并保护胰腺管腺癌.
科学领域:
- 癌症学
- 免疫学
- 细胞生物学
背景情况:
- 胰腺管腺癌 (PDA) 细胞通常逃避细胞亡,这是一个被编程的细胞死亡途径,以生存和繁殖.
- 在PDA病变发生过程中死细胞的作用和其作为治疗点的潜力仍然不清楚.
- 化学疗法,如金胺,用于治疗PDA,但癌细胞往往会产生抗药性.
研究的目的:
- 研究亡及其关键成分RIP1和RIP3在胰腺癌进展中的作用.
- 探索亡信号对瘤微环境和免疫细胞透的影响.
- 确定潜在的治疗策略,以向PDA中的死亡途径.
主要方法:
- 在PDA组织和细胞系中分析RIP1和RIP3的表达.
- 使用基因操纵 (RIP3删除,RIP1抑制) 和药物阻断的体外和体内研究.
- 评估瘤细胞增殖,瘤表型,免疫细胞透和化学激素表达 (CXCL1).
- 研究SAP130-Mincle信号轴及其在PDA中的作用.
主要成果:
- RIP1和RIP3在PDA中表达很高,并通过gemcitabine进行上调.
- 在实验室中,抑制亡 (RIP1/ RIP3阻断) 促进了癌细胞的增殖和侵袭性表型.
- 在体内,RIP3删除或RIP1抑制保护了PDA进展,导致具有高度免疫性的瘤微环境,并增加了骨髓细胞和T细胞的透.
- 死亡信号诱导了CXCL1的表达,导致了免疫抑制的瘤微环境;CXCL1的阻断保护了PDA.
- 取决于RIP1/RIP3的SAP130-Mincle轴促进了瘤发生,而Mincle删除则复制了RIP3删除的保护作用.
- 在RIP3或Mincle被删除后,抑制性巨细胞失去了其免疫抑制功能,T细胞对抗瘤免疫变得至关重要.
结论:
- 由RIP1和RIP3介导的亡,通过建立免疫抑制瘤微环境,在促进PDA进展方面发挥着关键作用.
- 向亡信号,包括CXCL1和SAP130-Mincle轴,可以将瘤微环境重新编程为抗瘤免疫反应.
- 抑制亡是一种有前途的胰腺癌治疗策略,有可能提高免疫治疗的疗效.
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