Unraveling the Expression Patterns of Immune Checkpoints Identifies New Subtypes and Emerging Therapeutic Indicators in Lung Adenocarcinoma

Immune checkpoint genes (ICGs) play pivotal roles in tumor immune microenvironment (TIME), and thus, targeting them represents a promising strategy for cancer immunotherapy. However, the genetic landscape of ICGs in lung adenocarcinoma (LUAD) is still unknown. Herein, we comprehensively evaluated the ICG expression profiles of 1439 LUAD samples and linked ICG expression patterns with infiltration of immune cells, clinical features, and response to immune checkpoint blockade (ICB). The ICGscore was developed to quantify ICG expression patterns of individual patient by principal component analysis algorithms. Three distinct ICG expression patterns and three ICG-related genomic clusters were determined, which were implicated in different clinical outcomes, level of immune infiltrates, and biological process. LUAD patients were subdivided into high- and low-ICGscore subgroups. Patients with higher ICGscore were characterized by favorable survival outcomes, increased immune cell infiltration, and enhanced expression of ICGs. Further analysis revealed that lower ICGscore was associated with greater tumor mutation loads and higher mutation rates of TTN, KEAP1, and ZFHX4. High ICGscore has the potential to be a robust indicator in clinical benefit of immunotherapy. Taken together, unraveling the ICG expression patterns will advance our understanding of heterogeneity of TIME and guides more effective immunotherapeutic strategies in LUAD.