Research Paper Volume 12, Issue 4 pp 3312—3339

Analysis of immune-related signatures of lung adenocarcinoma identified two distinct subtypes: implications for immune checkpoint blockade therapy

Qinghua Wang 1, , Meiling Li 1, , Meng Yang 2, , Yichen Yang 2, , Fengju Song 1, , Wei Zhang 3, , Xiangchun Li 2, , Kexin Chen 1, ,

  • 1 Department 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
  • 2 Tianjin Cancer Institute, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
  • 3 Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA

received: September 18, 2019 ; accepted: January 27, 2020 ; published: February 24, 2020 ;

https://doi.org/10.18632/aging.102814
How to Cite

Copyright © 2020 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

CTL: cytotoxic T lymphocytes; DDR: DNA damage repair; FDA: Food and Drug Administration; FDR: false discovery rate; GEO: Gene Expression Omnibus; GSEA: gene set enrichment analysis; LUAD: lung adenocarcinoma; MSigDB: Molecular Signatures Database; NMF: nonnegative matrix factorization; NSCLC: non-small-cell lung cancer; PD-L1: programmed death-ligand 1; RFE: recursive feature elimination; SMGs: significantly mutated genes; TCGA: The Cancer Genome Atlas; TIDE: Tumor Immune Dysfunction and Exclusion; TMB: tumor mutation burden.