A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL6 secreted from pancreatic stellate cells (PSC) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell–derived cytokine IL1α as an upstream mediator of IL6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL1R1, which is strongly expressed on stromal cells. Further, we show that IL1R1 inhibition using anakinra (recombinant IL1 receptor antagonist) significantly reduces stromal-derived IL6, thereby suppressing IL6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL1 in mediating tumor–stromal IL6/STAT3 cross-talk in the TME and provide a preclinical rationale for targeting IL1 signaling as a therapeutic strategy in PDAC.

中文翻译：

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在胰腺癌中通过 IL1 受体抑制靶向肿瘤间质 IL6/STAT3 信号传导

胰腺导管腺癌 (PDAC) 的一个标志是存在致密的促纤维增生基质，以及随之而来的癌细胞与其周围肿瘤微环境 (TME) 之间相互作用的改变，从而促进疾病进展、转移和化疗耐药。我们之前已经表明，胰腺星状细胞 (PSC) 分泌的 IL6 刺激肿瘤细胞中 STAT3 信号传导的激活，这是 PDAC 中治疗耐药性的既定机制。我们现在已经确定肿瘤细胞衍生的细胞因子 IL1α 作为 PSC 释放 IL6 的上游介质，其参与 TME 内的 STAT3 激活。在这里，我们表明 IL1α 在小鼠和人类 PDAC 肿瘤中均过表达，并与其在基质细胞上强烈表达的同源受体 IL1R1 结合。更远，我们显示使用阿那白滞素（重组 IL1 受体拮抗剂）抑制 IL1R1 可显着降低基质衍生的 IL6，从而抑制人 PDAC 细胞系中 IL6 依赖性 STAT3 的激活。Anakinra 治疗导致来自 Ptf1aCre/+；LSL-KrasG12D/+ 的胰腺肿瘤中 IL6 和活化的 STAT3 水平显着降低；Tgfbr2flox/flox (PKT) 小鼠。此外，在这种侵袭性 PDAC 遗传小鼠模型中，与载体治疗或阿那白滞素单一疗法相比，阿那白滞素与细胞毒性化学疗法的组合显着延长了总生存期。这些数据突出了 IL1 在介导 TME 中肿瘤间质 IL6/STAT3 串扰中的重要性，并为将 IL1 信号转导作为 PDAC 中的治疗策略提供了临床前依据。