Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells
Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells
复制标题
人类乳腺癌干细胞逃避 NK 细胞毒性的免疫逃逸的转移后果
DOI：
10.1158/0008-5472.can-13-2563
复制
发表时间：
2014-10-15
期刊：
影响因子：
11.2
通讯作者：
Bian, Xiu-Wu
中科院分区：
文献类型：
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作者：
Wang, Bin;Wang, Qiang;Bian, Xiu-Wu
乳腺癌干细胞（BCSC）在转移过程中起着至关重要的作用，但其潜在机制尚不清楚。在这里，我们报告了肿瘤浸润性自然杀伤（NK）细胞未能限制转移，并且与bcsc丰富的乳腺癌的治疗结果改善无关。由于MICA和MICB（刺激NK细胞受体NKG2D的两种配体）的表达减少，原代BCSCs对自体/异体NK细胞介导的细胞毒性具有抗性。此外，MICA/MICB在BCSCs中的下调是由异常表达的致癌miR20a介导的，这促进了BCSC对NK细胞毒性的抵抗并导致肺转移。乳腺癌细胞分化诱导剂全反式维甲酸恢复miR20a-MICA/MICB轴，使BCSC对NK细胞介导的杀伤敏感，从而减少免疫逃逸相关的BCSC转移。总之，我们的研究结果揭示了人类BCSC免疫逃逸的新机制，并确定了miR20a-MICA/MICB信号轴作为限制转移性乳腺癌的治疗靶点。(c) 2014年aacr。
Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. (C) 2014 AACR.