IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.
IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/1535-7163.mct-16-0899
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发表时间：
2017-09
影响因子：
5.7
通讯作者：
Beatty GL
中科院分区：
文献类型：
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作者：
Long KB;Tooker G;Tooker E;Luque SL;Lee JW;Pan X;Beatty GL
由 Janus 激酶/信号转导器和转录激活剂 (JAK/STAT) 信号激活介导的炎症是癌症化疗耐药的主要原因。我们研究了选择性阻断 IL-6 受体 (IL6R) 作为抑制 IL-6 诱导的 STAT 激活并克服胰腺导管腺癌 (PDAC) 化疗耐药性的策略的影响。为此，我们对 LSL-KrasG12D/+；LSL-Trp53R172H/+；Pdx-1Cre (KPC) 小鼠自发产生的肿瘤中的 STAT 激活进行了研究。使用免疫荧光显微镜和定量基因表达测定来评估 PDAC 患者的血浆激活人单核细胞中 STAT3/SOCS3 的能力。用 IL6R 阻断抗体（抗 IL6R）处理植入 KPC 衍生细胞系的 KPC 小鼠和同系小鼠（野生型和 IL6−/−）。分别使用超声检查和卡尺监测治疗对 KPC 小鼠和具有 KPC 衍生肿瘤植入物的小鼠肿瘤生长的影响。通过免疫组织化学分析肿瘤，以检测 STAT 激活、肿瘤活力和增殖的变化。我们发现 STAT3 是 KPC 小鼠 PDAC 肿瘤中最活跃的 STAT 蛋白。来自晚期 PDAC 患者的血浆刺激人单核细胞中 STAT3/SOCS3 的激活。在小鼠中，抗 IL6R 抗体靶向 Ly6Chi 单核细胞，抑制肿瘤细胞中 STAT3 的激活，并减少体内肿瘤细胞的增殖。 IL6R 阻断与化疗相结合可诱导肿瘤细胞凋亡、肿瘤消退并提高总体生存率。总体而言，我们发现 IL-6 信号传导驱动肿瘤细胞中 STAT3 激活并介导 PDAC 中的化疗耐药性。因此，使用抗 IL6R 抗体破坏 IL-6 信号传导有望改善 PDAC 的化疗疗效。
Inflammation mediated by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL-6 receptor (IL6R) as a strategy to inhibit IL-6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild-type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by immunohistochemistry to detect changes in STAT activation, tumor viability and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions and improved overall survival. Overall, we show that IL-6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL-6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC.