Abstract
Purpose
To demonstrate the biological function of Secreted Phosphoprotein 1(SPP1) and its immune suppressive role in the progression intrahepatic cholangiocarcinoma (ICC).
Methods
We collected 62,770 cells’ published transcriptome data of nine patients whose paired adjacent liver and tumor tissues were both available. We applied differential gene expression analysis to screen potential ICC marker genes, survival analysis to verify the prognostic value of SPP1, and correlation analysis to decipher factors that are related to SPP1 expression. The CellChat was used to distinguish interactions between cancer and T cells. CytoSig was applied to query cytokines that modulate CD44. Further, we established a proliferation score and correlated the score with inhibitory signals to determine the proliferation-suppressive function of SPP1-CD44.
Results
SPP1 expression is significantly upregulated in tumoral epitheliums, and patients with higher SPP1 expression have worse survival (P < 0.05). Tumor cells communicate with T cells via SPP1-CD44 interactions. The average expression of SPP1 in malignant cells (SPP1m) and CD44 in T cells (CD44t) is moderately negatively correlated with T cell proliferation score. Immunosuppressive cytokine TGFβ-3 identified as an inducer of CD44 and was significantly negatively correlated with proliferation score (R = − 0.88, P < 0.01), and the negative correlation was aggravated in samples with high CD44 expression.
Conclusion
SPP1 is a prognostic marker of ICC and is associated with the genome heterogeneity. SPP1-CD44 hinders sustained proliferation of T cells, but immunosuppressive T cells in the tumor microenvironment may evade this inhibition by reducing CD44 expression.
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Data availability
The published data used in this study were retrieved from the NCBI Gene Expression Omnibus database accession code GSE1387089. The remaining data are within the article or available from the authors upon request. Analysis scripts are available upon request from the corresponding author.
Abbreviations
- ICC:
-
Intrahepatic cholangiocarcinoma
- TME:
-
Tumor microenvironment
- SPP1:
-
Secreted Phosphoprotein 1
- TAM:
-
Tumor-associated macrophages
- CAFs:
-
Cancer-associated fibroblasts
- EGFR:
-
Epidermal growth factor receptor
- HIFs:
-
Hypoxia-inducible factors
- IDH:
-
Isocitrate dehydrogenase
- NK:
-
Natural killer
- scRNA-seq:
-
Single-cell RNA sequencing
- CNV:
-
Copy number variation
- DC:
-
Dendritic cells
- ITH:
-
Intratumoral heterogeneity
- SPP1m:
-
Expression of SPP1 in malignant cells
- CD44t:
-
Expression of CD44 in T cells
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Acknowledgements
We acknowledge TCGA and GEO database for providing their platforms and contributors for uploading their meaningful datasets. We thank Dr. Xiaona Lin and Dr. Qihui Sun (both are from South China University of Technology) for generously sharing their experience and codes.
Funding
This work was supported by China postdoctoral science foundation (No. 2022M710838).
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YL and MLC designed the outline and drafted the manuscript. MLC analyzed the data, performed the research, and designed the figures and tables. XNL and QHS offered professional suggestions to the manuscript. GDL and ZYY provided the language editing. All authors read and approved the final manuscript.
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Cheng, M., Liang, G., Yin, Z. et al. Immunosuppressive role of SPP1-CD44 in the tumor microenvironment of intrahepatic cholangiocarcinoma assessed by single-cell RNA sequencing. J Cancer Res Clin Oncol 149, 5497–5512 (2023). https://doi.org/10.1007/s00432-022-04498-w
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DOI: https://doi.org/10.1007/s00432-022-04498-w