Molecular subtypes based on ferroptosis-related genes and tumor microenvironment infiltration characterization in lung adenocarcinoma

Oncoimmunology. 2021 Sep 11;10(1):1959977. doi: 10.1080/2162402X.2021.1959977. eCollection 2021.


Recently, several molecular subtypes with different prognosis have been found in lung adenocarcinoma (LUAD). However, the characteristics of the ferroptosis molecular subtypes and the associated tumor microenvironment (TME) cell infiltration have not been fully studied in LUAD. Using 1160 lung adenocarcinoma samples, we explored the molecular subtypes mediated by ferroptosis-related genes, along with the associated TME cell infiltration. The ferroptosis score was constructed using the least absolute shrinkage and selection operator regression (LASSO) method to quantify the ferroptosis characteristics of a single tumor. Three different molecular subtypes related to ferroptosis, with different prognoses, were identified in LUAD. Analysis of TME cell infiltration revealed immune heterogeneity among the three subtypes. Cluster A was characterized by immunosuppression and was associated with stromal activation. Cluster C was characterized by a large number of immune cells infiltrating the TME, promoting tumor immune response, and it was significantly enriched in immune activation-related signaling pathways. Relatively less infiltration of immune cells was a feature of cluster B. The ferroptosis score can predict tumor subtype, immunity and prognosis. A low ferroptosis score was characterized by immune activation and good prognosis, as seen in the cluster C subtype. Relative immunosuppression and poor prognosis were the characteristics of a high ferroptosis score, as seen in cluster A and B subtypes. At the same time, the anti-PD-1/L1 immunotherapy cohort demonstrated that a low ferroptosis score was associated with higher efficacy of immunotherapy. The ferroptosis score is a promising biomarker that could be of great significance to determine the prognosis, molecular subtypes, TME cell infiltration characteristics and immunotherapy effects in patients with LUAD.

Keywords: Ferroptosis; immunotherapy; lung adenocarcinoma; molecular subtypes; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Ferroptosis*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms* / genetics
  • Tumor Microenvironment / genetics

Grants and funding

This study was funded by grants from the Key Scientific and Technological Projects in Nantong City, Jiangsu, China (No. MS22019015), Jiangsu Post-doctoral Foundation Research Project, China (No. 2019Z142), Clinical basic research youth project of Nantong University (No. 2019JQ002), Basic research project of Nantong Municipal Science (No. JCZ19103).