Abstract

Lung adenocarcinoma (LUAD) is one of the most common malignancies in the lung. T cell exhaustion (TEX) is an important immune escape mechanism that may be targeted to improve tumor immunotherapy. The present study investigated TEX?related genes in the tumor microenvironment to predict the prognosis of patients with LUAD. Data from 516 patients with LUAD were collected from The Cancer Genome Atlas database and classified them into TEX?C1 and TEX?C2 by unsupervised clustering based on the TEX?related genes. Compared with TEX?C1, TEX?C2 cluster had worse prognosis, with shorter overall and progression?free survival. Functional analysis revealed that upregulated genes in the TEX?C2 cluster were significantly enriched in tumor immune? and metabolism?related pathways. TEX?C2 cluster had a poor immune checkpoint blockade (ICB) response and a shorter survival after ICB treatment by Tumor Immune Dysfunction and Exclusion algorithm. A prognostic TEX?related gene signature was constructed for patients with LUAD by Least Absolute Shrinkage and Selection Operator regression analysis. B cell antigen receptor complex?associated protein β chain (CD79B) was considered an independent prognostic indicator; in the clinical correlation analysis, the effect of CD79B on prognosis was associated with advanced lung cancer, advanced age, female sex and patients with history of smoking. The overexpression of CD79B was associated with more infiltration of CD8⁺ T cells, M1 macrophages (the classically activated type 1, pro?inflammatory type), and less infiltration of M0 (undifferentiated) and M2 macrophages (the alternatively activated type 2, anti?inflammatory type) by CIBERSORT algorithm, which was also significantly correlated with gene markers of innate and adaptive immune cells, and higher levels of immune checkpoint genes. Upregulation of CD79B could inhibit the proliferation, migration and invasion capabilities and promote the apoptosis of LUAD cells, and induce M1?like tumor?associated macrophage (TAM) polarization. In conclusion, patients with LUAD in the TEX?C2 cluster had worse prognosis and adverse immune microenvironment. CD79B may be a potential prognostic indicator, which could inhibit malignant progression of LUAD cells and induce M1?like TAM polarization.