Clinical M2 Macrophage-Related Genes Can Serve as a Reliable Predictor of Lung Adenocarcinoma

Chaojie Xu; Lishan Song; Yubin Yang; Yi Liu; Dongchen Pei; Jiabang Liu; Jianhua Guo; Nan Liu; Xiaoyong Li; Yuchen Liu; Xuesong Li; Lin Yao; Zhengjun Kang

doi:10.3389/fonc.2022.919899

Clinical M2 Macrophage-Related Genes Can Serve as a Reliable Predictor of Lung Adenocarcinoma

Front Oncol. 2022 Jul 22:12:919899. doi: 10.3389/fonc.2022.919899. eCollection 2022.

Authors

Chaojie Xu¹, Lishan Song¹, Yubin Yang², Yi Liu¹, Dongchen Pei¹, Jiabang Liu³, Jianhua Guo¹, Nan Liu¹, Xiaoyong Li¹, Yuchen Liu⁴, Xuesong Li⁵, Lin Yao⁵, Zhengjun Kang¹

Affiliations

¹ The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
² Peking University First Hospital, Peking University, Beijing, China.
³ Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
⁴ Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
⁵ College of Pharmacy, Shantou University School of Medicine, Shantou, China.

Abstract

Background: Numerous studies have found that infiltrating M2 macrophages play an important role in the tumor progression of lung adenocarcinoma (LUAD). However, the roles of M2 macrophage infiltration and M2 macrophage-related genes in immunotherapy and clinical outcomes remain obscure.

Methods: Sample information was extracted from TCGA and GEO databases. The TIME landscape was revealed using the CIBERSORT algorithm. Weighted gene co-expression network analysis (WGCNA) was used to find M2 macrophage-related gene modules. Through univariate Cox regression, lasso regression analysis, and multivariate Cox regression, the genes strongly associated with the prognosis of LUAD were screened out. Risk score (RS) was calculated, and all samples were divided into high-risk group (HRG) and low-risk group (LRG) according to the median RS. External validation of RS was performed using GSE68571 data information. Prognostic nomogram based on risk signatures and other clinical information were constructed and validated with calibration curves. Potential associations of tumor mutational burden (TMB) and risk signatures were analyzed. Finally, the potential association of risk signatures with chemotherapy efficacy was investigated using the pRRophetic algorithm.

Results: Based on 504 samples extracted from TCGA database, 183 core genes were identified using WGCNA. Through a series of screening, two M2 macrophage-related genes (GRIA1 and CLEC3B) strongly correlated with LUAD prognosis were finally selected. RS was calculated, and prognostic risk nomogram including gender, age, T, N, M stage, clinical stage, and RS were constructed. The calibration curve shows that our constructed model has good performance. HRG patients were suitable for new ICI immunotherapy, while LRG was more suitable for CTLA4-immunosuppressive therapy alone. The half-maximal inhibitory concentrations (IC50) of the four chemotherapeutic drugs (metformin, cisplatin, paclitaxel, and gemcitabine) showed significant differences in HRG/LRG.

Conclusions: In conclusion, a comprehensive analysis of the role of M2 macrophages in tumor progression will help predict prognosis and facilitate the advancement of therapeutic techniques.

Keywords: M2 macrophages; WGCNA; immunotherapy; lung adenocarcinoma; risk score.