Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA.
Nat Commun. 2022 Feb 9;13(1):759. doi: 10.1038/s41467-022-28407-4.
Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate β-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, β-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer.
尽管免疫疗法在许多类型的癌症中取得了显著的成功，但胰腺导管腺癌尚未从中受益。先天免疫细胞对于抗肿瘤免疫监视至关重要，最近的研究表明，这些群体具有一种记忆形式，称为训练有素的先天免疫，它通过转录组学、表观遗传学和代谢重编程发生。在这里，我们证明酵母衍生的颗粒β-葡聚糖（一种诱导训练有素的先天免疫的物质）可以运送到胰腺，导致 CCR2 依赖性单核细胞/巨噬细胞流入胰腺，这些细胞表现出训练有素的先天免疫特征。这些细胞在暴露于肿瘤细胞和肿瘤衍生因子时可以被激活，并显示出对胰腺肿瘤细胞更强的细胞毒性。在胰腺导管腺癌的原位模型中，接受β-葡聚糖治疗的小鼠显示肿瘤负担显著降低，存活时间延长，当与免疫疗法结合使用时，效果进一步增强。这些发现描述了外周训练有素的先天免疫的动态机制和定位，并确定了训练有素的先天免疫在癌症中的应用。
