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Published on: February 7, 2021
Analysis of immune-related signatures of lung adenocarcinoma identified two distinct subtypes: implications for
Qinghua Wang1, Meiling Li1, Meng Yang2
1Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Abstract:
Immune checkpoint blockade (ICB) therapies have revolutionized the treatment of human cancers 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. Here we performed molecular subtyping and association analysis of LUAD from the Cancer Genome Atlas (TCGA) and validated findings from TCGA cohort in 9 independent validation cohorts. We conducted consensus molecular subtyping with nonnegative matrix factorization (NMF). Potential response of ICB therapy was estimated with Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. We identified 2 distinct subtypes of LUAD in TCGA cohort that were characterized by significantly different survival outcomes (i.e., high- and low-risk subtypes). The high-risk subtype was featured by lower TIDE score, upregulation of programmed death-ligand 1 (PD-L1) expression, and higher tumor mutation burden (TMB). The high-risk subtype also harbored significantly elevated cell cycle modulators CDK4/CDK6 and TP53 mutation. These observations were validated in 9 independent LUAD cohorts. Our findings suggest that immune checkpoint blockade therapy may be efficacious for high-risk subtype of LUAD patients.
Insights
This study identifies two lung adenocarcinoma (LUAD) subtypes. The high-risk subtype shows potential for effective immune checkpoint blockade (ICB) therapy due to specific molecular features.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade (ICB) therapies have transformed cancer treatment, including for lung adenocarcinoma (LUAD).
- However, a comprehensive understanding of LUAD immune subtypes and their correlation with ICB response is lacking.
Purpose of the Study:
- To perform molecular subtyping of LUAD and analyze its association with ICB response.
- To validate findings across multiple independent LUAD cohorts.
Main Methods:
- Consensus molecular subtyping using nonnegative matrix factorization (NMF).
- Estimation of ICB response potential using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm.
- Analysis of TCGA and 9 independent LUAD cohorts.
Main Results:
- Identified two distinct LUAD subtypes: high-risk and low-risk, with differing survival outcomes.
- The high-risk subtype exhibited lower TIDE scores, increased programmed death-ligand 1 (PD-L1) expression, and higher tumor mutation burden (TMB).
- High-risk subtype also showed elevated CDK4/CDK6 and TP53 mutations, consistent across validation cohorts.
Conclusions:
- The identified LUAD subtypes offer a novel framework for understanding LUAD immunity.
- The high-risk subtype presents a promising candidate for targeted immune checkpoint blockade therapy.
