Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer.
Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer.
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DOI：
10.18632/oncotarget.14960
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发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Tamura Y
中科院分区：
文献类型：
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作者：
Tanaka T;Kutomi G;Kajiwara T;Kukita K;Kochin V;Kanaseki T;Tsukahara T;Hirohashi Y;Torigoe T;Okamoto Y;Hirata K;Sato N;Tamura Y
据报道，许多人类癌症具有免疫检查点分子程序性死亡配体1（PD-L1）的增强表达，其结合免疫细胞上表达的程序性细胞死亡-1（PD-1）。PD-L1/PD-1通过诱导T细胞凋亡和耐受在抑制抗肿瘤免疫中发挥作用。因此，阐明PD-L1在癌细胞上表达的机制至关重要。ERO 1-α是一种位于内质网的氧化酶。它在多种肿瘤类型中过表达，并与PDI协作在二硫键形成中发挥作用。在这里，我们研究了ERO 1-α对PD-L1表达和免疫逃逸的影响。我们证明ERO 1-α通过促进PD-L1内的氧化蛋白折叠来增强PD-L1的表达。此外，我们发现ERO 1-α的过表达增加了HIF-1α蛋白的表达，导致PD-L1 mRNA和蛋白的增加。在临床病例中，我们观察到ERO 1-α在三阴性乳腺癌中的表达与PD-L1的表达相关。此外，当ERO 1-α耗尽时，肿瘤PD-L1诱导的表达PD-1的Jurkat白血病T细胞的凋亡被抑制。结果表明，靶向肿瘤细胞中的ERO 1-α可能是癌症免疫治疗的新方法。因此，ERO 1-α在肿瘤免疫抑制中的作用有待进一步研究。
Many human cancers have been reported to have enhanced expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1), which binds to programmed cell death-1 (PD-1) expressed on immune cells. PD-L1/PD-1 plays a role in inhibition of antitumor immunity by inducing T cell apoptosis and tolerance. Thus, it is crucial to elucidate mechanisms of PD-L1 expression on cancer cells. ERO1-α is an oxidase located in the endoplasmic reticulum. It is overexpressed in a variety of tumor types and it plays a role in disulfide bond formation in collaboration with PDI. Here, we investigated the influence of ERO1-α on expression of PD-L1 and immune escape. We demonstrated that ERO1-α augmented the expression of PD-L1 via facilitation of oxidative protein folding within PD-L1. In addition, we showed that overexpression of ERO1-α increased HIF-1α protein expression, resulting in an increase of PD-L1 mRNA as well as protein. In clinical cases, we observed that the expression of ERO1-α in triple negative breast cancer was related to the expression of PD-L1. Moreover, apoptosis of Jurkat leukemia T cells, which express PD-1, induced by tumor PD-L1 was inhibited when ERO1-α was depleted. The results suggest that targeting ERO1-α in tumor cells can be a novel approach for cancer immunotherapy. Therefore, the role of ERO1-α in tumor-mediated immunosuppression should be further explored.