Integrated Analysis of M2 Macrophage-related Gene Prognostic Model and Single-cell Sequence to Predict Immunotherapy Response in Lung Adenocarcinoma

Overview

Journal Front Genet

Date 2025 Feb 18

PMID 39963673

Authors

Meifang Li

Zhiping Wang

Bin Huang

Yanyun Lai

Meng Zhang

Cheng Lin

Affiliations

Soon will be listed here.

Abstract

Background: Lung adenocarcinoma (LUAD) patients have high heterogeneity. The significance and clinical value of M2 macrophage-related genes in LUAD require further exploration. We aimed to construct a prognostic signature to predict the immunotherapy efficacy and prognosis in LUAD.

Methods: GSE26939 and GSE19188 chips were downloaded from the Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis were used to screen M2 macrophage-related prognostic genes. A signature based on M2 macrophage-related prognostic genes was established and used to predict the prognosis and immunotherapy efficacy in LUAD.

Results: Twenty-two M2 macrophage-related genes associated with the prognosis of LUAD were confirmed using WGCNA, and then two molecular subtypes were identified with significantly different survival, gene expressions, and clinic characteristics were classified. LASSO analysis identified nine M2 macrophage-related prognostic genes to establish a risk signature, classifying patients into low- and high-risk groups. Data indicated that low-risk patients had better survival. Moreover, the signature was an independent prognostic factor for LUAD and a potential biomarker for patients receiving immunotherapy. Single-cell transcriptome analysis may provide important information on molecular subtypes and heterogeneity.

Conclusion: Risk signature based on M2 macrophage-related genes is a valuable tool for predicting prognosis and immunotherapy response in patients with LUAD.

References

Mino-Kenudson M, Schalper K, Cooper W, Dacic S, Hirsch F, Jain D . Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective From the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2022; 17(12):1335-1354. DOI: 10.1016/j.jtho.2022.09.109. View

Liu S, Zheng M, Pan Y, Liu S, Li Y, Wu Y . Emerging evidence and treatment paradigm of non-small cell lung cancer. J Hematol Oncol. 2023; 16(1):40. PMC: 10108547. DOI: 10.1186/s13045-023-01436-2. View

Doroshow D, Bhalla S, Beasley M, Sholl L, Kerr K, Gnjatic S . PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021; 18(6):345-362. DOI: 10.1038/s41571-021-00473-5. View

Dora D, Ligeti B, Kovacs T, Revisnyei P, Galffy G, Dulka E . Non-small cell lung cancer patients treated with Anti-PD1 immunotherapy show distinct microbial signatures and metabolic pathways according to progression-free survival and PD-L1 status. Oncoimmunology. 2023; 12(1):2204746. PMC: 10184596. DOI: 10.1080/2162402X.2023.2204746. View

Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang C . M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer. Exp Ther Med. 2019; 18(6):4490-4498. PMC: 6862535. DOI: 10.3892/etm.2019.8068. View

Xu F, Wei Y, Tang Z, Liu B, Dong J . Tumor‑associated macrophages in lung cancer: Friend or foe? (Review). Mol Med Rep. 2020; 22(5):4107-4115. PMC: 7533506. DOI: 10.3892/mmr.2020.11518. View

Thummalapalli R, Ricciuti B, Bandlamudi C, Muldoon D, Rizvi H, Elkrief A . Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2023; 29(21):4408-4418. PMC: 10618656. DOI: 10.1158/1078-0432.CCR-23-1207. View

Zhu H, Zheng C, Liu H, Kong F, Kong S, Chen F . Significance of macrophage infiltration in the prognosis of lung adenocarcinoma patients evaluated by scRNA and bulkRNA analysis. Front Immunol. 2022; 13:1028440. PMC: 9597471. DOI: 10.3389/fimmu.2022.1028440. View

Sanchez-Magraner L, Gumuzio J, Miles J, Quimi N, Del Prado P, Abad-Villar M . Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2023; 41(14):2561-2570. PMC: 10414696. DOI: 10.1200/JCO.22.01748. View

10.

Xiang Y, Wang G, Liu B, Zheng H, Liu Q, Ma G . Macrophage-Related Gene Signatures for Predicting Prognosis and Immunotherapy of Lung Adenocarcinoma by Machine Learning and Bioinformatics. J Inflamm Res. 2024; 17:737-754. PMC: 10859764. DOI: 10.2147/JIR.S443240. View

11.

Yang L, Dong Y, Li Y, Wang D, Liu S, Wang D . IL-10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF-κB/Notch1 pathway in non-small cell lung cancer. Int J Cancer. 2019; 145(4):1099-1110. DOI: 10.1002/ijc.32151. View

12.

Beyeen A, Adzemovic M, Ockinger J, Stridh P, Becanovic K, Laaksonen H . IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation. J Immunol. 2010; 185(11):6883-90. DOI: 10.4049/jimmunol.1001392. View

13.

Zhao C, Pan Y, Liu L, Zhang J, Wu X, Liu Y . Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy. Small. 2024; 20(31):e2311702. DOI: 10.1002/smll.202311702. View

14.

Wu G, He M, Ren K, Ma H, Xue Q . Inducible Co-Stimulator ICOS Expression Correlates with Immune Cell Infiltration and Can Predict Prognosis in Lung Adenocarcinoma. Int J Gen Med. 2022; 15:3739-3751. PMC: 8995865. DOI: 10.2147/IJGM.S349441. View

15.

Festekdjian T, Bonavida B . Targeting the Depletion of M2 Macrophages: Implication in Cancer Immunotherapy. Crit Rev Oncog. 2024; 29(4):55-73. DOI: 10.1615/CritRevOncog.2024053580. View

16.

Wang J, Li D, Cang H, Guo B . Crosstalk between cancer and immune cells: Role of tumor-associated macrophages in the tumor microenvironment. Cancer Med. 2019; 8(10):4709-4721. PMC: 6712467. DOI: 10.1002/cam4.2327. View

17.

Gordon M, Smith M, Nastoupil L . Follicular lymphoma: The long and winding road leading to your cure?. Blood Rev. 2022; 57:100992. DOI: 10.1016/j.blre.2022.100992. View

18.

Yamaguchi Y, Gibson J, Ou K, Lopez L, Ng R, Leggett N . PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages. J Immunother Cancer. 2022; 10(6). PMC: 9226933. DOI: 10.1136/jitc-2021-004400. View

19.

Breuer K, Foroushani A, Laird M, Chen C, Sribnaia A, Lo R . InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation. Nucleic Acids Res. 2012; 41(Database issue):D1228-33. PMC: 3531080. DOI: 10.1093/nar/gks1147. View

20.

Dimitrakopoulos F, Kottorou A, Antonacopoulou A, Panagopoulos N, Scopa C, Kalofonou M . Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients. J Clin Med. 2019; 8(5). PMC: 6572708. DOI: 10.3390/jcm8050741. View