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Abstract：
Tenascin C (TNC) is an extracellular matrix glycoprotein that is highly expressed in cancer stroma and is associated with tumor progression in pancreatic adenocarcinoma (PAAD). In this study, we aimed to investigate the potential involvement of TNC in the response to immune checkpoint inhibitors (ICI) among PAAD patients. Transcriptomic profiles were obtained from public databases and analyzed to compare TNC mRNA levels between tumor and normal tissues. Bioinformatic programs were used to predict paracrine communications between cancer cells and cancer-associated fibroblasts (CAFs), and the Tumor Immune Dysfunction and Exclusion (TIDE) score was calculated to predict response to ICI treatment in PAAD patients. An independent immunotherapeutic cohort was used to validate the clinical impact of the signatures. Results showed that TNC mRNA levels were significantly upregulated in tumors compared to normal tissues in PAAD, and patients with high TNC expression had significantly shorter overall survival than those with low TNC expression (P = 0.0125). TNC was predominantly expressed in CAFs of PAAD patients and was found to potentially enhance the epithelial-mesenchymal transition (EMT) of cancer cells via integrin receptors, contributing to resistance to ICI treatment. Patients with high TNC expression and high ITGαV or ITGB3 expression were associated with poor response to ICI therapy. In conclusion, these findings suggest that TNC-high CAFs play a crucial role in tumor progression and resistance to ICI therapy in PAAD patients, and targeting TNC and its interactions with cancer cells may provide a potential strategy for improving the efficacy of ICI therapy in PAAD.
摘要：
生腱蛋白C（TNC）是一种在癌间质中高表达的细胞外基质糖蛋白，与胰腺癌（PAAD）的肿瘤进展有关。在这项研究中,我们旨在研究在PAAD患者中,TNC可能参与免疫检查点抑制剂(ICI)的应答.转录组谱从公共数据库获得并分析以比较肿瘤和正常组织之间的TNCmRNA水平。生物信息学程序用于预测癌细胞和癌症相关成纤维细胞（CAF）之间的旁分泌通讯，计算肿瘤免疫功能障碍和排除（TIDE）评分以预测PAAD患者对ICI治疗的反应。使用独立的免疫治疗组来验证签名的临床影响。结果表明，与正常组织相比，PAAD中肿瘤中的TNCmRNA水平明显上调，TNC高表达患者的总生存期明显短于TNC低表达患者(P=0.0125)。TNC主要在PAAD患者的CAFs中表达，并被发现可能通过整合素受体增强癌细胞的上皮-间质转化（EMT）。导致对ICI治疗的抵抗。具有高TNC表达和高ITGαV或ITGB3表达的患者与ICI治疗的应答差相关。总之,这些发现表明，TNC高CAFs在PAAD患者的肿瘤进展和对ICI治疗的抵抗中起着至关重要的作用，靶向TNC及其与癌细胞的相互作用可能为提高ICI治疗PAAD的疗效提供潜在策略。
