STING和非坏死性mlkl介导的机制改善树突状细胞成熟和杀死癌细胞

IF 3.7 3区 医学 Q2 IMMUNOLOGY
Trine S. Jensen, Marlene F. Laursen, Lea Schort, Agnieszka J. Banasik, Ralf Agger, Martin R. Jakobsen, Emil Kofod-Olsen
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引用次数: 0

摘要

cGAS-STING通路的激活通过肿瘤浸润性dc的成熟在抗肿瘤免疫中发挥重要作用。DC吞噬垂死癌细胞释放的细胞外DNA,支持cGAS-STING通路的激活和伴随的DC成熟。肿瘤微环境中的细胞外DNA主要来源于经历不受控制的坏死或程序性炎症性死亡的细胞,如坏死性死亡,当细胞凋亡途径被抑制时可诱导。在这里,我们报道了caspase抑制启动了dc中RIPK1/3、MLKL和STING信号轴的激活,导致成熟,而不需要任何进一步的成熟刺激,如LPS或TNF-α。值得注意的是,这些信号事件不会诱导DC死亡,这表明RIPK1-RIPK3-MLKL通路具有非坏死性作用,并与STING通路产生了新的串扰。在DC/癌细胞共培养中抑制Caspase导致DC成熟,诱导TNF-α分泌,其传递共同信号诱导癌细胞坏死。综上所述,我们发现STING和坏死下垂通路在DC成熟过程中存在协同作用机制,激活坏死下垂通路对癌细胞和DC具有相反的作用,为癌症免疫治疗提供了新的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells

STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells

Activation of the cGAS-STING pathway plays an important role in antitumor immunity through maturation of tumor-infiltrating DCs. DCs engulf extracellular DNA released by dying cancer cells, supporting activation of the cGAS-STING pathway and concomitant DC maturation. Extracellular DNA in the tumor microenvironment is primarily derived from cells undergoing uncontrolled necrosis or programmed inflammatory death, such as necroptosis, which can be induced when apoptosis pathways are inhibited. Here, we report that caspase inhibition primes activation of a RIPK1/3, MLKL, and STING signaling axis in DCs, resulting in maturation without the need for any further maturation stimuli such as LPS or TNF-α. Notably, these signaling events do not induce DC death, indicating a nonnecroptotic role of the RIPK1-RIPK3-MLKL pathway and novel crosstalk with the STING pathway. Caspase inhibition in DC/cancer cell co-cultures results in DC maturation, inducing TNF-α secretion, which delivers the co-signal to induce cancer cell necroptosis. In summary, we find a collaborative mechanism of the STING and necroptosis pathway in DC maturation, and that activation of the necroptosis pathway has opposite effects on cancer cells and DCs, proposing a possibility for new targets in cancer immunotherapy.

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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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