Comen Elizabeth, Wojnarowicz Paulina, Seshan Venkatraman E, Shah Riddhi, Coker Courtney, Norton Larry, Benezra Robert
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
NPJ Breast Cancer. 2016 Apr 20;2:16009. doi: 10.1038/npjbcancer.2016.9. eCollection 2016.
We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors 'prime' neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNFα), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity . RNA-seq analyses found protein kinase C iota ( to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. has been implicated in NADPH oxidase assembly, required for neutrophil-mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis.
我们之前在乳腺癌模型中已证明中性粒细胞在小鼠肺转移前微环境中具有新的抗转移作用。在此，我们在人类乳腺癌背景下拓展了这些发现。我们评估了90例新诊断乳腺癌患者、24例导管癌患者、56例转移性乳腺癌患者以及64例无癌症病史女性的中性粒细胞的细胞毒性。我们报告称，转移性和新诊断乳腺癌患者的中性粒细胞比无癌个体的中性粒细胞具有显著更强的细胞毒性。我们推测肿瘤分泌因子使中性粒细胞“致敏”从而具有细胞毒性。为了鉴定这些因子，我们检测了54例乳腺癌患者和35例无癌对照者血清中的细胞因子。肿瘤坏死因子（TNFα）、单核细胞趋化蛋白-1（MCP-1，即CCL2）和白细胞介素1受体拮抗剂（IL1RA）与细胞毒性显著相关，并直接刺激中性粒细胞的细胞毒性。RNA测序分析发现，与无癌个体的中性粒细胞相比，蛋白激酶C ι（PRKCI）在患者中性粒细胞中过表达。PRKCI与中性粒细胞介导的细胞毒性所需的NADPH氧化酶组装有关。用肿瘤坏死因子（TNF）处理人类中性粒细胞可诱导PRKCI表达水平低的样本中的PRKCI表达和细胞毒性。迄今为止，这项工作首次证明了中性粒细胞在一大群乳腺癌患者外周血中的细胞毒性作用，并且特定细胞因子似乎介导了对中性粒细胞细胞毒性的刺激。有必要进行进一步的功能研究，以确定刺激中性粒细胞细胞毒性的临床相关方法，作为对抗疾病进展和转移的有效屏障。
