Single-cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCA^phl) and peripheral small duct type (iCCA^pps). S100P + SPP1- iCCA^phl has significantly reduced levels of infiltrating CD4⁺ T cells, CD56⁺ NK cells, and increased CCL18⁺ macrophages and PD1⁺CD8⁺ T cells compared to S100P-SPP1 + iCCA^pps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCA^pps has significantly more SPP1⁺ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1- iCCA^phl. Moreover, S100P-SPP1 + iCCA^pps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.