Immunosuppressive role of SPP1-CD44 in the tumor microenvironment of intrahepatic cholangiocarcinoma assessed by single-cell RNA sequencing

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.

Keywords: CD44; Intrahepatic cholangiocarcinoma; SPP1; Single-cell RNA sequencing; Tumor microenvironment.