Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

中文翻译：

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热休克蛋白 90 抑制改变胰腺星状细胞的活化并增强 PD-1 阻断在胰腺癌中的功效。

胰腺导管腺癌 (PDAC) 具有显着的纤维化间质，这是肿瘤、免疫和胰腺星状细胞 (PSC) 或癌症相关成纤维细胞 (CAF) 相互作用的结果。靶向基质内存在的炎症通路可以改善效应免疫细胞对 PDAC 的访问和对免疫治疗的反应。热休克蛋白 90 (Hsp90) 是一种伴侣蛋白，是胰腺癌的多功能靶点。Hsp90 调节与肿瘤和免疫系统相关的多种细胞过程。然而，迄今为止，尚未详细探讨 Hsp90 在 PSC/CAF 中的作用。我们假设 Hsp90 抑制会限制炎症信号，从而重新编程 PDAC 肿瘤微环境以增强对 PD-1 阻断的敏感性。用 Hsp90 抑制剂 XL888 治疗永生化和原发性患者 PSC/CAF 可降低 IL6，这是一种在体外在转录和蛋白质水平上协调 PDAC 免疫变化的关键细胞因子。XL888 直接限制 PSC/CAF 生长并降低 Jak/STAT 和 MAPK 信号中间体以及通过免疫印迹确定的 α-SMA 表达。XL888 和抗 PD-1 的联合治疗对携带同基因皮下 (Panc02) 或原位 (KPC-Luc) 肿瘤的 C57BL/6 小鼠有效。来自接受 XL888 和抗 PD-1 治疗的小鼠的肿瘤具有显着增加的 CD8+ 和 CD4+ T 细胞浸润以及以与免疫反应和趋化性相关的基因上调为特征的独特转录谱。