小柯机器人

北大尹玉新团队揭示肿瘤免疫逃逸新机制
2020-01-15 11:30

磷酸酶PAC1作为T细胞抑制剂,减弱宿主抗肿瘤免疫,这一成果由北京大学尹玉新团队取得。相关论文在线发表在2020年1月13日的《自然—免疫学》上。

研究人员发现双重特异性磷酸酶2(DUSP2;也称为活化细胞磷酸酶1,PAC1)可以作为T细胞抗肿瘤免疫的免疫检查点。PAC1在耗竭的肿瘤浸润淋巴细胞中选择性上调,这与癌症患者的不良预后相关。PAC1hi效应T细胞失去其增殖和效应器能力,并转化为耗竭的T细胞。敲出PAC1可增强免疫反应并降低小鼠的癌症易感性。通过激活EGR1,肿瘤微环境中过量的活性氧会诱导PAC1的表达,从而募集Mi-2β核小体重塑和组蛋白去乙酰化酶复合物,最终导致效应T细胞的染色质重塑。这项研究表明PAC1是一种在表观遗传学上发挥功能的免疫调节剂,并证实了PAC1可作为癌症免疫治疗的靶点。

据了解,癌细胞通过抑制T细胞效应子的功能来破坏免疫监视。因此,阐明T细胞功能耗竭的机制对于癌症免疫治疗至关重要。

附:英文原文

Title: The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity

Author: Dan Lu, Liang Liu, Yizhe Sun, Jia Song, Qi Yin, Guangze Zhang, Fang Qi, Zixi Hu, Zeliang Yang, Zhe Zhou, Ying Hu, Lianhai Zhang, Jiafu Ji, Xuyang Zhao, Yan Jin, Michael A. McNutt, Yuxin Yin

Issue&Volume: 2020-01-13

Abstract: Cancer cells subvert immune surveillance through inhibition of T cell effector function. Elucidation of the mechanism of T cell dysfunction is therefore central to cancer immunotherapy. Here, we report that dual specificity phosphatase 2 (DUSP2; also known as phosphatase of activated cells 1, PAC1) acts as an immune checkpoint in T cell antitumor immunity. PAC1 is selectively upregulated in exhausted tumor-infiltrating lymphocytes and is associated with poor prognosis of patients with cancer. PAC1hi effector T cells lose their proliferative and effector capacities and convert into exhausted T cells. Deletion of PAC1 enhances immune responses and reduces cancer susceptibility in mice. Through activation of EGR1, excessive reactive oxygen species in the tumor microenvironment induce expression of PAC1, which recruits the Mi-2β nucleosome-remodeling and histone-deacetylase complex, eventually leading to chromatin remodeling of effector T cells. Our study demonstrates that PAC1 is an epigenetic immune regulator and highlights the importance of targeting PAC1 in cancer immunotherapy.

DOI: 10.1038/s41590-019-0577-9

Source: https://www.nature.com/articles/s41590-019-0577-9

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:31.25
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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