A Mechanism of Hypoxia-Mediated Escape from Adaptive Immunity in Cancer Cells
A Mechanism of Hypoxia-Mediated Escape from Adaptive Immunity in Cancer Cells
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DOI：
10.1158/0008-5472.can-13-0992
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Graham, Charles H.
中科院分区：
文献类型：
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作者：
Barsoum, Ivraym B.;Smallwood, Chelsea A.;Graham, Charles H.
免疫逃逸是癌症的基本特征，其中机制知识是不完整的。在这里，我们描述了一种新的机制，缺氧有助于肿瘤免疫逃避细胞毒性T淋巴细胞（CTL）。将人或鼠癌细胞暴露于缺氧24小时导致免疫抑制分子程序性细胞死亡配体-1（PD-L1;也称为B7-H1）以依赖于转录因子缺氧诱导因子-1 α（HIF-1 α）的方式上调。体内研究还证实了肿瘤中HIF-1 α和PD-L1的细胞共定位。缺氧诱导的PD-L1在癌细胞中的表达增加了它们对CTL介导的裂解的抗性。使用三硝酸甘油酯（GTN）（一种一氧化氮（NO）信号激动剂，已知可以阻断缺氧细胞中HIF-1 α的积累），我们阻止了缺氧诱导的PD-L1表达并降低了对CTL介导的溶解的抵抗力。此外，GTN的经皮给药减弱了小鼠中的肿瘤生长。我们发现，通过暴露于缺氧诱导肿瘤细胞中PD-L1的更高表达导致共培养的CTL和Jurkat白血病T细胞的凋亡增加。通过阻断PD-L1与PD-1（T细胞上的PD-L1受体）的相互作用或通过添加GTN来防止细胞凋亡的增加。我们的研究结果指出了缺氧/HIF-1在驱动免疫逃避CTL中的作用，并且他们提出了一种新的癌症免疫疗法，通过施用NO模拟物来阻断缺氧肿瘤细胞中的PD-L1表达。
Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha). In vivo studies also demonstrated cellular colocalization of HIF-1 alpha and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1 alpha accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.