Single-cell transcriptomic analysis suggests two molecularly distinct 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.