The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity
The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity
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磷酸酶 PAC1 作为 T 细胞抑制剂并减弱宿主的抗肿瘤免疫力。
DOI：
10.1038/s41590-019-0577-9
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发表时间：
2020-01-13
影响因子：
30.5
通讯作者：
Yin, Yuxin
中科院分区：
文献类型：
--
作者：
Lu, Dan;Liu, Liang;Yin, Yuxin
癌细胞通过抑制T细胞效应功能破坏免疫监视。因此，阐明T细胞功能障碍的机制是癌症免疫治疗的核心。在这里，我们报道了双特异性磷酸酶2 （DUSP2，也称为活化细胞磷酸酶1，PAC1）在T细胞抗肿瘤免疫中起免疫检查点的作用。PAC1在衰竭的肿瘤浸润淋巴细胞中选择性上调，与癌症患者预后不良有关。PAC1（hi）效应T细胞失去增殖和效应能力，转化为耗竭的T细胞。在小鼠中，缺失PAC1可增强免疫反应并降低癌症易感性。通过激活EGR1，肿瘤微环境中过多的活性氧诱导PAC1的表达，PAC1招募Mi-2 β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。我们的研究表明，PAC1是一种表观遗传免疫调节剂，并强调了靶向PAC1在癌症免疫治疗中的重要性。Yin和他的同事们发现，磷酸酶PAC1 （DUSP2）在细胞毒性T细胞中作为一个检查点来抑制它们的抗肿瘤功能。
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. PAC1(hi) 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-2 beta 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.Yin and colleagues show that the phosphatase PAC1 (DUSP2) acts as a checkpoint in cytotoxic T cells to restrain their antitumor function.