Molecular characterization based on tumor microenvironment-related signatures for guiding immunotherapy and therapeutic resistance in lung adenocarcinoma

Yamin Jie; Jianing Wu; Dongxue An; Man Li; Hongjiang He; Duo Wang; Anxin Gu; Mingyan E

doi:10.3389/fphar.2023.1099927

Molecular characterization based on tumor microenvironment-related signatures for guiding immunotherapy and therapeutic resistance in lung adenocarcinoma

Front Pharmacol. 2023 Jan 16:14:1099927. doi: 10.3389/fphar.2023.1099927. eCollection 2023.

Authors

Yamin Jie¹, Jianing Wu², Dongxue An¹, Man Li³, Hongjiang He⁴, Duo Wang⁵, Anxin Gu², Mingyan E²

Affiliations

¹ Department of Radiation Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
² Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
³ Department of Endoscopy, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
⁵ Department of Neurology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.

Abstract

Background: Although the role of tumor microenvironment in lung adenocarcinoma (LUAD) has been explored in a number of studies, the value of TME-related signatures in immunotherapy has not been comprehensively characterized. Materials and Methods: Consensus clustering was conducted to characterize TME-based molecular subtypes using transcription data of LUAD samples. The biological pathways and immune microenvironment were assessed by CIBERSORT, ESTIMATE, and gene set enrichment analysis. A TME-related risk model was established through the algorithms of least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). Results: Four TME-based molecular subtypes including C1, C2, C3, and C4 were identified, and they showed distinct overall survival, genomic characteristics, DNA methylation pattern, immune microenvironment, and biological pathways. C1 had the worst prognosis and high tumor proliferation rate. C3 and C4 had higher enrichment of anti-tumor signatures compared to C1 and C2. C4 had evidently low enrichment of epithelial-mesenchymal transition (EMT) signature and tumor proliferation rate. C3 was predicted to be more sensitive to immunotherapy compared with other subtypes. C1 is more sensitive to chemotherapy drugs, including Docetaxel, Vinorelbine and Cisplatin, while C3 is more sensitive to Paclitaxel. A five-gene risk model was constructed, which showed a favorable performance in three independent datasets. Low-risk group showed a longer overall survival, more infiltrated immune cells, and higher response to immunotherapy than high-risk group. Conclusion: This study comprehensively characterized the molecular features of LUAD patients based on TME-related signatures, demonstrating the potential of TME-based signatures in exploring the mechanisms of LUAD development. The TME-related risk model was of clinical value to predict LUAD prognosis and guide immunotherapy.

Keywords: DNA methylation; cisplatin; immunotherapy; lung adenocarcinoma; molecular subtypes; paclitaxel.

Grants and funding

The present study was supported by the National Natural Science Foundation of China (82072027); Heilongjiang Postdoctoral Fund (LBH-Z18120); Heilongjiang Applied Technology Research and Development Program Project (GA20C009); Haiyan Medical Research Foundation (JJZD 2021-03); Beijing Medical Award Foundation (YXT2-2021-0166-0183).