Increased Nuclear Transporter KPNA2 Contributes to Tumor Immune Evasion by Enhancing PD-L1 Expression in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells in vitro, the in vivo tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.

胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，以其对治疗的高抗性和低反应性而闻名。肿瘤免疫逃逸是设计有效的抗癌治疗策略的主要障碍。核转运蛋白α2（KPNA2）是核转运蛋白家族的成员，在多种人类癌症中升高，并加速癌变。然而，KPNA2在PDAC中的具体作用仍不清楚。在本研究中，通过分析基因表达综合数据库（GEO）数据集，我们发现与相邻的非肿瘤组织相比，KPNA2在PDAC中的表达显著上调，并且其高表达与不良的生存结果相关。通过免疫组化染色在人类患者样本和KPC小鼠模型中也发现了类似的KPNA2表达模式。尽管在体外KPNA2的敲低未能损害PDAC细胞的活力和迁移能力，但在体内肿瘤生长受到显著阻碍，并且通过沉默KPNA2，免疫检查点配体PD - L1的表达降低。此外，我们发现KPNA2通过介导STAT3的核转位来调节PD - L1的表达。总之，我们的数据表明KPNA2有潜力作为PDAC诊断的一个有前景的生物标志物。