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受体阻滞剂增强胰腺导管腺癌的化疗效果

由JAK / STAT信号激活介导的炎症是癌症中化学疗法耐药性的主要原因。我们研究了选择性阻断IL6受体（IL6R）作为抑制IL6诱导的STAT激活并克服胰腺导管腺癌（PDAC）的化学耐药性的策略的影响。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测定法评估了来自PDAC患者的血浆激活人类单核细胞中STAT3 / SOCS3的能力。用IL6R阻断抗体（抗IL6R）处理植入了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来源的肿瘤植入物的小鼠中肿瘤生长的影响。通过IHC分析肿瘤，以检测STAT激活，肿瘤生存力和增殖的变化。我们发现STAT3是来自KPC小鼠的PDAC肿瘤中活化最强的STAT蛋白。晚期PDAC患者的血浆刺激了人类单核细胞中的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活化，并降低体内肿瘤细胞的增殖。IL6R阻断与化学疗法相结合可诱导肿瘤细胞凋亡，肿瘤消退并改善总生存期。总体而言，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信号传导有望改善PDAC的化疗疗效。分子癌疗法；16（9）; 1898–908年。©2017 AACR。