Cancer cells educate natural killer cells to a metastasis-promoting cell state
Cancer cells educate natural killer cells to a metastasis-promoting cell state
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DOI：
10.1083/jcb.202001134
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发表时间：
2020-09-07
影响因子：
7.8
通讯作者：
Ewald, Andrew Josef
中科院分区：
文献类型：
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作者：
Chan, Isaac S.;Knutsdottir, Hildur;Ewald, Andrew Josef
自然杀伤（NK）细胞具有有效的抗肿瘤和抗转移活性。目前尚不完全清楚癌细胞如何逃避 NK 细胞的监视。使用离体和体内转移模型，我们确定 keratin-14(+) 乳腺癌细胞容易受到 NK 细胞的攻击。然后我们发现，接触癌细胞会导致 NK 细胞失去细胞毒性能力并促进转移生长。基因表达比较显示，健康 NK 细胞具有活跃的 NK 细胞分子表型，而肿瘤暴露 (teNK) 细胞类似于静息 NK 细胞。 teNK 细胞和肿瘤细胞之间的受体配体分析揭示了多个潜在靶点。接下来我们表明，使用靶向 TIGIT 的抗体、靶向 KLRG1 的抗体或 DNA 甲基转移酶 (DMNT) 小分子抑制剂进行治疗均可减少集落形成。 DNMT 抑制剂与抗 TIGIT 或抗 KLRG1 抗体的组合进一步降低了转移潜力。我们建议针对这些途径的 NK 定向疗法在辅助治疗中可有效预防转移复发。
Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14(+) breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor-ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence.