Unité INSERM U753, Institut de Cancérologie Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France.
Cancer Res. 2012 Sep 15;72(18):4629-41. doi: 10.1158/0008-5472.CAN-12-1383. Epub 2012 Sep 7.
Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve.
肿瘤微环境中的缺氧在肿瘤细胞免疫逃逸机制的演变中起着核心作用。在这项研究中，我们报告了 miR-210 作为一种受肺癌和黑色素瘤缺氧调节的 miRNA 的定义，记录了它参与削弱肿瘤细胞对特异性抗原细胞毒性 T 淋巴细胞（CTL）溶解的敏感性。miR-210 在人类肿瘤组织的缺氧区域被诱导。其在缺氧细胞中的衰减显著恢复了对自体 CTL 介导的溶解的敏感性，而与肿瘤细胞识别和 CTL 反应性无关。使用转录组分析、argonaute 蛋白免疫沉淀和荧光素酶报告基因检测的综合方法表明，PTPN1、HOXA1 和 TP53I11 是受缺氧细胞调控的 miR-210 靶基因。支持它们在介导 miR-210 的免疫抑制作用方面的主要重要性，PTPN1、HOXA1 和 TP53I11 的协同沉默显著降低了肿瘤细胞对 CTL 介导的溶解的敏感性。我们的研究结果表明，miR-210 的诱导如何将缺氧与 CTL 介导的溶解的免疫逃逸联系起来，通过提供一种机制理解，说明了这种 miRNA 如何在肿瘤缺氧区域介导免疫抑制，已知癌症干细胞样细胞和转移细胞行为在这些区域中演变。
