Analysis of Immune-Related Signatures of Lung Adenocarcinoma Identifies Two Distinct Immunophenotypic Subtypes: Implications for Immune Checkpoint Blockade Therapy

Abstract

Background: Immune checkpoint blockade (ICB) therapies have revolutionized the treatment of human cancer including lung adenocarcinoma (LUAD). However, our understanding of the immune subtyping of LUAD and its association with clinical response of immune checkpoint inhibitor remains incomplete. Methods: We performed molecular subtyping of LUAD by analyzing immune infiltrating profiles of one LUAD cohorts from The Cancer Genome Atlas (TCGA) (discovery set) and 7 cohorts from Gene Expression Omnibus (GEO) (validation sets). Consensus molecular subtyping was performed using nonnegative matrix factorization (NMF). We used Tumor immune dysfunction and exclusion (TIDE) algorithm to predict potential response of ICB therapy and gene set enrichment analysis (GSEA) to identify dysregulated pathways. Findings: We identified 2 distinct subtypes of LUAD in TCGA cohorts that were characterized by significantly different immune infiltrating patterns and survival outcomes (i.e., high- and low-risk subtypes). The high-risk subtype was featured by upregulation of programmed death-ligand 1 (PD-L1) expression, higher infiltration of tumor infiltrating lymphocytes (TIL), and higher tumor mutation burden (TMB). Further analysis indicated the high-risk subtype harbored significantly activated cell cycle and TP53 mutation. These observations were validated in 7 additional independent LUAD cohorts. Interpretation: We identified 2 subtypes of LUAD featured by different immune infiltrating signatures and molecular mechanisms. Immune checkpoint blockade therapy may be efficacious for high-risk subtype of LUAD patients. Funding Statement: The study has been supported by the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40) and National Natural Science Foundation of China (NSFC) (no. 31801117). Declaration of Interests: The authors state: None reported. Ethics Approval Statement: Not required.