Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shanxi, China.
Department of Clinical Medicine, School of Medicine, Shihezi University, Shihezi, China.
J Gene Med. 2023 Jul;25(7):e3496. doi: 10.1002/jgm.3496. Epub 2023 May 2.
Oesophageal adenocarcinoma (EAC) is one of the most common malignant tumours, and the number of patients is increasing year by year. T-cell exhaustion (TEX) is an important risk factor for tumour immunosuppression and invasion, but its underlying mechanism in the pathogenesis of EAC is not clear.
Unsupervised clustering was performed to screen relevant genes based on Gene Set Variation Analysis scores of the three pathways of the HALLMARK gene set IL2/IFNG/TNFA. Multiple enrichment analyses and data combinations were used to depict the relationship between TEX-related risk models and CIBERSORTx immune infiltrating cells. In addition, to explore the impact of TEX on EAC therapeutic resistance, we assessed the impact of TEX risk models on the therapeutic sensitivity of various novel drugs using single-cell sequencing and searched for their potential therapeutic targets and cellular communication.
Four risk clusters of EAC patients were identified by unsupervised clustering and searched for potential TEX-related genes. Based on this, LASSO regression and decision trees were used to construct risk prognostic models containing a total of three TEX-associated genes in EAC. The results showed that TEX risk scores were significantly associated with the survival prognosis of EAC patients in both the Cancer Genome Atlas dataset and the independent validation set of Gene Expression Omnibus. Immune infiltration and cell communication analyses identified mast cell resting as a protective factor in TEX, and pathway enrichment analyses showed that the TEX risk model was highly associated with multiple chemokines as well as inflammation-associated pathways. In addition, higher TEX risk scores were associated with a weak responsiveness to immunotherapy.
We describe the immune infiltration, prognostic significance and potential possible mechanisms of TEX in the EAC patient population. This is a novel attempt to promote the development of novel therapeutic modalities and immunological target construction for oesophageal adenocarcinoma. It is expected to make a potential contribution to advancing the exploration of immunological mechanisms and the opening of target drugs in EAC.
食管腺癌（EAC）是最常见的恶性肿瘤之一，且患者人数逐年增加。T 细胞耗竭（TEX）是肿瘤免疫抑制和侵袭的一个重要危险因素，但其在 EAC 发病机制中的潜在机制尚不清楚。
基于 HALLMARK 基因集 IL2/IFNG/TNFA 三个通路的基因集变异分析评分，进行无监督聚类以筛选相关基因。采用多种富集分析和数据组合，描绘 TEX 相关风险模型与 CIBERSORTx 免疫浸润细胞之间的关系。此外，为了探讨 TEX 对 EAC 治疗耐药性的影响，我们使用单细胞测序评估 TEX 风险模型对各种新型药物治疗敏感性的影响，并寻找其潜在的治疗靶点和细胞通讯。
通过无监督聚类确定了 4 个 EAC 患者风险聚类，并搜索了潜在的 TEX 相关基因。在此基础上，采用 LASSO 回归和决策树构建了包含 EAC 中 3 个 TEX 相关基因的风险预后模型。结果表明，TEX 风险评分与癌症基因组图谱数据集和基因表达综合数据库独立验证集中 EAC 患者的生存预后显著相关。免疫浸润和细胞通讯分析鉴定出静止肥大细胞是 TEX 的保护因素，通路富集分析表明 TEX 风险模型与多种趋化因子以及炎症相关通路高度相关。此外，TEX 风险评分较高与免疫治疗反应性较弱相关。
我们描述了 TEX 在 EAC 患者人群中的免疫浸润、预后意义和潜在可能机制。这是促进食管腺癌新型治疗方式和免疫靶标构建的新尝试，有望为探索免疫机制和 EAC 靶标药物的开发做出潜在贡献。
