A signature-based classification of lung adenocarcinoma that stratifies tumor immunity

Immune-related subgroup classification in immune checkpoint blockade (ICB) therapy is largely inconclusive in lung adenocarcinoma (LUAD).

First, the single-sample Gene Set Enrichment Analysis (ssGSEA) and K-means algorithms were used to identify immune-based subtypes for the LUAD cohort based on the immunogenomic profiling of 29 immune signatures from The Cancer Genome Atlas (TCGA) database (n = 504). Second, we examined the prognostic and predictive value of immune-based subtypes using bioinformatics analysis. Survival analysis and additional COX proportional hazards regression analysis were conducted for LUAD. Then, the immune score, tumor-infiltrating immune cells (TIICs), and immune checkpoint expression of the three subtypes were analyzed. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) of the differentially expressed genes (DEGs) between three immune-based subtypes were subsequently analyzed for functional enrichment pathways.

A total of three immune-based subtypes with distinct immune signatures have been identified for LUAD and designated as cluster 1 (C1), cluster 2 (C2), and cluster 3 (C3). Patients in C3 had higher stromal, immune, and ESTIMATE scores, whereas those in C1 had the opposite. Patients in C1 had an enrichment of macrophages M0 and activation of dendritic cells, whereas tumors in C3 had an enrichment of CD8⁺ T cells, activation of CD4⁺ memory T cells, and macrophages M1. C3 had a higher immune cell infiltration and a better survival prognosis than other subtypes. Furthermore, patients in C3 had higher expression levels of immune checkpoint proteins such as PD-L1, PD1, CTLA4, LAG3, IDO1, and HAVCR2. No significant differences were found in cluster TMB scores. We also found that immune-related pathways were enriched in C3.

LUAD subtypes based on immune signatures may aid in the development of novel treatment strategies for LUAD.