Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia.
Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia.
Int J Mol Sci. 2022 Jan 29;23(3):1565. doi: 10.3390/ijms23031565.
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis.
胆囊癌 (GBC) 是最常见和侵袭性的胆道癌之一，预后极差。目前正在进行的临床试验正在评估几种选定的免疫检查点抑制剂 (ICI) 作为单一疗法治疗 GBC 患者。然而，只有一部分患者从中受益。为了提高 ICI 治疗反应，需要探索赋予对免疫检查点 (IC) 阻断耐药性的分子机制。上皮-间充质转化 (EMT) 程序和癌症干细胞 (CSC) 已被认为是赋予 ICI 治疗耐药性的关键过程。然而，在 GBC 中，EMT-CSC-IC 轴尚未得到明确阐明。本研究旨在研究与 CSC 和 EMT 相关的异常表达的 ICs。我们成功地利用 3 维培养系统富集了 CSCs，并利用人 GBC NOZ 细胞系建立了一个可逆转的 EMT 模型。值得注意的是，ICs CD73 和 PD-L1 与 CSC 和 EMT 表型密切相关。CD73 或 PD-L1 的敲低降低了贴壁单层和无锚定球体的增殖和迁移能力。总之，阻断 CD73 和 PD-L1 为针对具有 CSC 和 EMT 表型的高度侵袭性群体提供了一种有前途的治疗策略，以改善 GBC 患者的预后。
