A new immune signature for survival prediction and immune checkpoint molecules in lung adenocarcinoma

Abstract

Background: Lung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer. The prognostic signature could be reliable to stratify LUAD patients according to risk, which helps the management of the systematic treatments. In this study, a systematic and reliable immune signature was performed to estimate the prognostic stratification in LUAD.

Methods: The profiles of immune-related genes for patients with LUAD were used as one TCGA training set: n = 494, other validation set 1: n = 226 and validation set 2: n = 398. Univariate Cox survival analysis was used to identify the candidate immune-related genes from each cohort. Then, the immune signature was developed and validated in the training and validation sets.

Results: In this study, functional analysis showed that immune-related genes involved in immune regulation and MAPK signaling pathway. A prognostic signature based on 10 immune-related genes was established in the training set and patients were divided into high-risk and low-risk groups. Our 10 immune-related gene signature was significantly related to worse survival, especially during early-stage tumors. Further stratification analyses revealed that this 10 immune-related gene signature was still an effective tool for predicting prognosis in smoking or nonsmoking patients, patients with KRAS mutation or KRAS wild-type, and patients with EGFR mutation or EGFR wild-type. Our signature was negatively correlated with B cell, CD4+ T cell, CD8+ T cell, neutrophil, dendritic cell (DC), and macrophage immune infiltration, and immune checkpoint molecules PD-1 and CTLA-4 (P < 0.05).

Conclusions: These findings suggested that our signature was a promising biomarker for prognosis prediction and can facilitate the management of immunotherapy in LUAD.

Keywords: Immune; Immune checkpoint molecules; Lung adenocarcinoma; Prediction; Prognosis; Signature.

Fig. 1

Functional enrichment analysis of immune-related genes in LUAD. a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. b Gene ontology (GO) analysis on biological process (BP), cellular component (CC), and molecular function (MF)

Fig. 2

The prognostic signature based on 10 immune-related genes in LUAD. a The distribution and survival status of patients for the immune-related gene signature. b Time-dependent ROC results at 1, 3, and 5 years. c Kaplan–Meier curves between the high-risk and low-risk groups

Fig. 3

Kaplan-Meier analyses of LUAD patients with age, gender, and smoking behavior, including a ≥ 65 years, b < 65 years, c male, d female, e smoking, and f nonsmoking

Fig. 4

Kaplan–Meier analyses of LUAD patients with stage, KRAS mutation status, and EGFR mutation status, including a stage 3–4, b stage 1–2, c KRAS mutation, d KRAS wild-type, e EGFR mutation, and f EGFR wild-type

Fig. 5

Correlation between our signature and tumor-infiltrating immune cells. a Association between risk score and B cells. b Association between risk score and CD4+ T cells. c Association between risk score and CD8+ T cells. d Association between risk score and Neutrophils. e Association between risk score and dendritic cells (DCs). f Association between risk score and Macrophages

Fig. 6

Correlation between our signature and known immune checkpoint genes. a Association between risk score and PD-1. b Association between risk score and CTLA-4. c Association of each immune checkpoint gene. “x” for no correlation; blue for negative correlation; red for positive correlation