Single-cell profiling reveals the trajectory of FOLR2-expressing tumor-associated macrophages to regulatory T cells in the progression of lung adenocarcinoma.

Abstract

An immunosuppressive microenvironment enriched with regulatory CD4+ T lymphocytes (Tregs) facilitates the progression of lung adenocarcinoma (LUAD). This study aims to investigate the cellular mechanism underlying the formation of the immunosuppressive microenvironment in LUAD. LUAD samples (n = 12) and normal lung samples (n = 3) were obtained from patients with different pathological stages of LUAD. Single-cell RNA sequencing was performed to classify cellular components and analyze the transcriptomes, including transcription factors/targets and chemokine ligands/receptors, followed by bioinformatics study such as pseudotime analysis. Myeloid cells and T cells were the most abundant cell types in tumors and normal lung tissues, while tumor-associated macrophage-folate receptor 2 (TAM-FOLR2) and CD4+ nuclear receptor subfamily 4 group A member 3 (NR4A3) exhibited sharp increases in invasive adenocarcinoma (IA). The enrichment of TAM-FOLR2 in IA might result from alveolar resident macrophage-resistin (ARM-RETN) transformation and recruitment of dendritic cells (DCs) and other TAMs, as evidenced by temporal trajectories and differential expression profiles of chemokine ligands/receptors versus those in the early stages of tumors. High expression of CCL17/19/22 was observed in IA as well as in DCs, along with the strong interaction of TAM-FOLR2 with DCs. The results of pseudotime analysis suggested that CD4+NR4A3 might potentially convert to CD4+FOXP3, further supported by the high expression of NR4A3 target genes in CD4+FOXP3 cells. This study provides a single-cell transcriptome atlas from preinvasive to invasive LUAD and reveals a potential ARM-RETN/TAM-FOLR2/DCs/CD4+NR4A3/CD4+FOXP3 trajectory in shaping the immune suppressive microenvironment along the pathogenesis of LUAD.

• Authors: Chan Xiang, Min Zhang, Zhanxian Shang, Shengnan Chen, Jikai Zhao, Bowen Ding, Dong Jiang, Qian Zhu, Haohua Teng, Lei Zhu, Jinchen Shao, Ruiying Zhao, Min Ye, Yang Yu, Yuchen Han
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 8 Pg. 493 (08 02 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 37532692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Folate Receptor 2
• Ligands
• Chemokines
• Forkhead Transcription Factors
• FOLR2 protein, human

Topics

• Humans
• T-Lymphocytes, Regulatory
• Folate Receptor 2
• Ligands
• Tumor-Associated Macrophages
• Adenocarcinoma of Lung (genetics)
• Adenocarcinoma (genetics)
• Lung Neoplasms (genetics)
• Chemokines (genetics)
• Forkhead Transcription Factors (genetics)
• Tumor Microenvironment (genetics)