Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell-Mediated Lysis
Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell-Mediated Lysis
复制标题
DOI：
10.1158/0008-5472.can-12-2432
复制
发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Chouaib, Salem
中科院分区：
文献类型：
--
作者：
Akalay, Intissar;Janji, Bassam;Chouaib, Salem
上皮-间质转化（EMT）介导癌细胞的侵袭、转移和耐药性，但其对免疫监视的影响尚未研究。在这项研究中，我们研究了这种模式的上皮细胞可塑性对靶细胞裂解细胞毒性T淋巴细胞（CTL）的功能后果。在MCF-7人乳腺癌细胞的各种衍生物中获得EMT表型与显著的形态学变化和肌动蛋白细胞骨架重塑相关，其中存在的CD 24（-）/CD 44（+）/ALDH（+）干细胞群体相对于亲本细胞表现出更高程度的EMT。引人注目的是，这种表型的获得也与CTL介导的肿瘤细胞溶解的抑制有关。抗性细胞在与CTL的免疫突触形成中表现出衰减，沿着靶细胞中自噬的诱导。这种反应对于CTL介导的裂解的易感性至关重要，因为siRNA介导的beclin 1沉默抑制靶细胞中的自噬恢复了它们对CTL诱导的裂解的易感性。我们的研究结果表明，除了促进侵袭和转移外，EMT还深刻地改变了癌细胞对T细胞介导的免疫监视的易感性。此外，他们揭示了EMT和自噬作为免疫策略的概念领域，以阻止免疫逃逸。Cancer Res; 73（8）; 2418-27. (C)2013年AACR。
Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF-7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24(-)/CD44(+)/ALDH(+) stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape. Cancer Res; 73(8); 2418-27. (C) 2013 AACR.