Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, Jiangsu, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
Drug Resist Updat. 2024 Mar;73:101040. doi: 10.1016/j.drup.2023.101040. Epub 2024 Jan 9.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the treatment of PDAC ICB resistance.
Enrichment of MHC class I was detected by RNA sequence and verified by RT-qPCR and immunoblotting in NDRG1-knockdown human pancreatic cancer cell lines. The protein degradation mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and immunolocalization. The roles of NDRG1 and MHC-I in immunotherapy were investigated by orthotopic solid tumors, histology, immunohistochemistry, multiplex immunofluorescence staining and flow cytometry.
Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of CD8 + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. In PDAC patients, NDRG1 expression correlates with high MHC-1 expression and better survival.
Our results reveal NDRG1 in PDAC cancer cells as a tumor suppressor and suggest that pharmaceutically targeting NDRG1 is a promising way to overcome pancreatic cancer resistance to immunotherapy and provides a potential therapeutic strategy for the treatment of pancreatic cancer patients.
胰腺导管腺癌（PDAC）是一种致命的疾病，对免疫检查点阻断（ICB）治疗具有耐药性。新出现的证据表明，NDRG1 可能是开发用于治疗 PDAC 的新疗法的重要靶点。在此，我们研究了 NDRG1 和 Combretastatin A-4（CA-4）在治疗 PDAC ICB 耐药中的新作用。
通过 RNA 序列检测 MHC 类 I 分子的富集，并通过 RT-qPCR 和免疫印迹进行验证。在 NDRG1 敲低的人胰腺癌细胞系中，通过刺激各种抑制剂发现蛋白降解模式，并通过免疫沉淀和免疫定位发现自噬降解途径。通过原位实体瘤、组织学、免疫组织化学、多重免疫荧光染色和流式细胞术研究 NDRG1 和 MHC-I 在免疫治疗中的作用。
在这里，我们鉴定了 NDRG1 在胰腺导管腺癌（PDAC）细胞中通过溶酶体-自噬依赖性降解激活主要组织相容性复合体 I 类（MHC-I）表达的先前未描述的作用。在 PDAC 的小鼠模型中，肿瘤细胞过表达或 NDRG1 的药物激活均可导致肿瘤细胞中 MHC-1 的上调，从而促进 CD8+T 细胞的浸润和活性，增强抗肿瘤免疫，并克服对 ICB 治疗的耐药性。此外，CA-4 和 ICB 的联合治疗克服了胰腺癌对 ICB 治疗的耐药性。在 PDAC 患者中，NDRG1 表达与 MHC-1 表达水平高和生存时间长相关。
我们的结果揭示了 PDAC 癌细胞中的 NDRG1 是一种肿瘤抑制因子，并表明药物靶向 NDRG1 是克服胰腺癌对免疫治疗耐药性的一种很有前途的方法，并为治疗胰腺癌患者提供了一种潜在的治疗策略。
