Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response.
Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response.
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DOI：
10.1158/0008-5472.can-11-4135
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Molldrem JJ
中科院分区：
文献类型：
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作者：
Mittendorf EA;Alatrash G;Qiao N;Wu Y;Sukhumalchandra P;St John LS;Philips AV;Xiao H;Zhang M;Ruisaard K;Clise-Dwyer K;Lu S;Molldrem JJ
肿瘤相关中性粒细胞（TAN）对肿瘤适应性免疫的影响知之甚少。在这项研究中，我们报告的结果的病理生物学基础的预后意义的中性粒细胞弹性蛋白酶（NE），丝氨酸蛋白酶发现在中性粒细胞颗粒，在模型中的细胞周期蛋白E过表达的乳腺癌。我们确定NE在乳腺癌组织中由TAN表达，但在乳腺癌细胞中不表达。NE通过细胞周期蛋白E衍生的HLA-A2限制性肽（ILLDWLMEV）特异性的细胞毒性T淋巴细胞（CTL）调节乳腺癌细胞的杀伤。乳腺癌细胞表现出显着的抗原特异性摄取NE的微环境，是独立的NE酶活性。此外，NE摄取增加了低分子量形式的细胞周期蛋白E的表达，并增强了对肽特异性CTL裂解的敏感性，表明细胞周期蛋白E肽天然存在于乳腺癌细胞上。总之，我们的研究结果揭示了一种以前未知的抗肿瘤适应性免疫机制，该机制将癌细胞对炎症介质的摄取与针对重要乳腺癌抗原的有效细胞溶解反应联系起来。
There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiological basis for the prognostic significance of neutrophil elastase (NE), a serine protease found in neutrophil granules, in a model of cyclin E-overexpressing breast cancer. We established that NE was expressed by TAN within breast cancer tissues but not by breast cancer cells. NE modulated killing of breast cancer cells by cytotoxic T lymphocytes (CTL) specific for cyclin E-derived HLA-A2 restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of NE from the microenvironment that was independent of NE enzymatic activity. Further, NE uptake increased expression of low molecular weight forms of cyclin E and enhanced susceptibility to peptide-specific CTL lysis, suggesting that cyclin E peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an inflammatory mediator to an effective cytolytic response against an important breast cancer antigen.