Different sensitivities of senescent breast cancer cells to immune cell-mediated cytotoxicity
Different sensitivities of senescent breast cancer cells to immune cell-mediated cytotoxicity
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DOI：
10.1111/cas.14116
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发表时间：
2019-07-23
期刊：
影响因子：
5.7
通讯作者：
Harada, Mamoru
中科院分区：
文献类型：
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作者：
Inao, Touko;Kotani, Hitoshi;Harada, Mamoru
衰老是一种生长停滞的状态，不仅在正常细胞中，而且在衰老或压力下也会在癌细胞中引起，从而引发 DNA 损伤。尽管生长受到抑制，衰老的癌细胞仍然通过产生细胞因子和生长因子来促进肿瘤的形成和复发。这种状态被称为衰老相关的分泌表型。在这项研究中，我们检查了衰老的人类乳腺癌细胞对免疫细胞介导的细胞毒性的敏感性。阿霉素 (DXR) 处理可诱导 2 种人类乳腺癌细胞系 MDA-MB-231 和 BT-549 衰老，并诱导 γ H2AX 表达和 p21 或 p16 表达增加。 DXR 治疗还诱导衰老相关 β-半乳糖苷酶的表达，并促进促炎细胞因子的产生。重要的是，DXR处理的衰老MDA-MB-231细胞对两种类型的免疫细胞介导的细胞毒性表现出更高的敏感性：激活的CD4(+) T细胞的细胞毒性和自然杀伤细胞的Ab依赖性细胞毒性。这种对细胞毒性敏感性的增加部分依赖于肿瘤坏死因子相关的凋亡诱导配体和穿孔素。在使用诱导衰老的细胞周期蛋白依赖性激酶 4/6 抑制剂 abemaciclib 治疗后，并未观察到这种敏感性的增加。此外，用 DXR（而非 abemaciclib）治疗可降低癌细胞中抗凋亡蛋白的表达。这些结果表明 DXR 和 abemaciclib 诱导乳腺癌细胞衰老，但它们对免疫细胞介导的细胞毒性的敏感性不同。这些发现可以为抗癌免疫疗法与化疗药物或分子靶向药物相结合提供指导。
Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of gamma H2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated beta-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4(+) T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.