Immunogenic Cell Death Signature Predicts Survival and Reveals the Role of VEGFA + Mast Cells in Lung Adenocarcinoma

Overview

Journal Sci Rep

Specialty Science

Date 2025 Feb 28

PMID 40021802

Authors

Meng Zhang

Guowei Zhou

Yantao Xu

Benliang Wei

Qian Liu

Guanxiong Zhang

Ruimin Chang

Affiliations

Soon will be listed here.

Abstract

Lung cancer is prevalent worldwide and is a major cause of cancer-related mortality. Despite being the primary model for immunotherapy research, the response rates of lung cancer patients to immunotherapy are unsatisfactory. Furthermore, research on immunogenic cell death (ICD) in lung cancer is limited, which limits the development of strategies that combine ICD-related therapies with immunotherapy. In this study, we compiled and summarized 69 genes associated with ICD and developed an IRS. Across seven independent datasets, the IRS was identified as an independent prognostic factor. IRS was positively associated with multiple tumor proliferation pathways and negatively associated with immune-related pathways. Additionally, IRS negatively correlated with the infiltration of various immune cells, supporting its association with survival outcomes. Based on the correlation between IRS and immune activity, we validated the ability of IRS to predict immunotherapy efficacy across seven immunotherapy datasets and demonstrated that patients who respond to immunotherapy tend to have a lower IRS. Moreover, utilizing single-cell RNA sequencing, we revealed the role of mast cells in the TME with the highest IRS. Through interactions with various receptors on macrophages, endothelial cells, and tumor cells, mast cells promote tumor progression, providing a comprehensive explanation for poor prognosis and lack of response to immunotherapy in patients with high IRS. Our study offers new guidance for combination therapies in lung adenocarcinoma patients and elucidated the mechanism by which mast cells contribute to cancer development within the TME.

References

Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Buque Martinez A . Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer. 2020; 8(1). PMC: 7064135. DOI: 10.1136/jitc-2019-000337. View

Levantini E, Maroni G, Del Re M, Tenen D . EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol. 2022; 85:253-275. DOI: 10.1016/j.semcancer.2022.04.002. View

Zhu J, Fan Y, Xiong Y, Wang W, Chen J, Xia Y . Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp Mol Med. 2022; 54(11):2060-2076. PMC: 9722784. DOI: 10.1038/s12276-022-00896-9. View

Ravi A, Hellmann M, Arniella M, Holton M, Freeman S, Naranbhai V . Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nat Genet. 2023; 55(5):807-819. PMC: 10181943. DOI: 10.1038/s41588-023-01355-5. View

Goel H, Mercurio A . VEGF targets the tumour cell. Nat Rev Cancer. 2013; 13(12):871-82. PMC: 4011842. DOI: 10.1038/nrc3627. View

Prat A, Navarro A, Pare L, Reguart N, Galvan P, Pascual T . Immune-Related Gene Expression Profiling After PD-1 Blockade in Non-Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma. Cancer Res. 2017; 77(13):3540-3550. DOI: 10.1158/0008-5472.CAN-16-3556. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Hu J, Zhang L, Xia H, Yan Y, Zhu X, Sun F . Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med. 2023; 15(1):14. PMC: 9985263. DOI: 10.1186/s13073-023-01164-9. View

10.

Schabath M, Welsh E, Fulp W, Chen L, Teer J, Thompson Z . Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene. 2015; 35(24):3209-16. PMC: 4837098. DOI: 10.1038/onc.2015.375. View

11.

Sato M, Larsen J, Lee W, Sun H, Shames D, Dalvi M . Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. Mol Cancer Res. 2013; 11(6):638-50. PMC: 3687022. DOI: 10.1158/1541-7786.MCR-12-0634-T. View

12.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

13.

Miao D, Margolis C, Gao W, Voss M, Li W, Martini D . Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018; 359(6377):801-806. PMC: 6035749. DOI: 10.1126/science.aan5951. View

14.

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

15.

Shedden K, Taylor J, Enkemann S, Tsao M, Yeatman T, Gerald W . Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008; 14(8):822-7. PMC: 2667337. DOI: 10.1038/nm.1790. View

16.

Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y . A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3):792-809.e23. DOI: 10.1016/j.cell.2021.01.010. View

17.

Venteicher A, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin M . Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017; 355(6332). PMC: 5519096. DOI: 10.1126/science.aai8478. View

18.

Browaeys R, Saelens W, Saeys Y . NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2019; 17(2):159-162. DOI: 10.1038/s41592-019-0667-5. View

19.

Stahler A, Stintzing S, Modest D, Ricard I, Giessen-Jung C, Kapaun C . Amphiregulin Expression Is a Predictive Biomarker for Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials. Clin Cancer Res. 2020; 26(24):6559-6567. DOI: 10.1158/1078-0432.CCR-20-2748. View

20.

. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511(7511):543-50. PMC: 4231481. DOI: 10.1038/nature13385. View