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.

中文翻译：

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NDRG1 通过抑制 MHC-1 的 ATG9A 依赖性降解来克服胰腺导管腺癌免疫治疗的耐药性


胰腺导管腺癌 (PDAC) 是一种对免疫检查点阻断 (ICB) 疗法具有抵抗力的致命疾病。新的证据表明 NDRG1 可能是开发 PDAC 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。在 NDRG1 敲低的人胰腺癌细胞系中，通过 RNA 序列检测 MHC I 类富集，并通过 RT-qPCR 和免疫印迹进行验证。通过各种抑制剂的刺激发现蛋白质降解模式，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了 NDRG1 和 MHC-I 在免疫治疗中的作用。在这里，我们发现了 NDRG1 在通过溶酶体自噬依赖性降解激活胰腺导管腺癌细胞 (PDAC) 细胞中主要组织相容性复合物 1 类 (MHC-1) 表达中的先前未描述的作用。在PDAC小鼠模型中，肿瘤细胞过表达或NDRG1的药理激活导致肿瘤细胞中MHC-1上调，进而促进CD8+T细胞的浸润和活性，增强抗肿瘤免疫，克服ICB耐药性治疗。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 高表达和更好的生存相关。 我们的结果揭示了 PDAC 癌细胞中的 NDRG1 作为肿瘤抑制因子，并表明以 NDRG1 为靶点的药物是克服胰腺癌对免疫治疗耐药性的有希望的方法，并为胰腺癌患者的治疗提供了潜在的治疗策略。