T-cell exhaustion: A potential target biomarker of the tumour microenvironment affecting oesophageal adenocarcinoma.

Abstract

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.