Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-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 IHC 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 IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.

中文翻译：

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IL6 受体阻断剂可增强胰腺导管腺癌的化疗疗效

由 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 IL6 受体 (IL6R) 作为抑制 IL6 诱导的 STAT 激活和克服胰腺导管腺癌 (PDAC) 化学抗性的策略的影响。为此，在 LSL-KrasG12D/+；LSL-Trp53R172H/+；Pdx-1Cre (KPC) 小鼠中自发产生的肿瘤中研究了 STAT 激活。使用免疫荧光显微镜和定量基因表达分析评估了来自 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 小鼠和同基因小鼠（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 IHC 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 肿瘤中最活化的 STAT 蛋白。来自晚期 PDAC 患者的血浆刺激了人单核细胞中的 STAT3/SOCS3 激活。在小鼠中，抗 IL6R 抗体靶向 Ly6Chi 单核细胞，抑制肿瘤细胞中的 STAT3 激活，并降低体内肿瘤细胞增殖。IL6R 阻断联合化疗诱导肿瘤细胞凋亡、肿瘤消退并改善总体存活率。总的来说，我们表明 IL6 信号驱动肿瘤细胞中的 STAT3 激活并介导 PDAC 中的化学抗性。因此，使用抗 IL6R 抗体破坏 IL6 信号传导有望提高 PDAC 的化疗疗效。摩尔癌症治疗; 16(9); 1898-908。©2017 AACR。