Identification of SPP1 + macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics


Jin H., Kim W., Yuan M., Li X., Yang H., Li M., ...Daha Fazla

Frontiers in Immunology, cilt.15, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 15
  • Basım Tarihi: 2024
  • Doi Numarası: 10.3389/fimmu.2024.1446453
  • Dergi Adı: Frontiers in Immunology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, CAB Abstracts, EMBASE, MEDLINE, Directory of Open Access Journals
  • Anahtar Kelimeler: co-expression network, hepatocellular carcinoma, macrophage heterogeneity, single-cell sequencing, tumor-associated macrophage
  • Atatürk Üniversitesi Adresli: Evet

Özet

Introduction: Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown. Methods: Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC. Results: In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1+ macrophages as an unfavorable cell type, while VCAN+ macrophages, C1QA+ macrophages, and CD8+ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1+ macrophages, inhibits CD8+ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype. Discussion: This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.