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. The molecular classification and tumour microenvironment in intrahepatic cholangiocarcinoma (iCCA) need further characterisation. Here, the authors perform single cell RNA-sequencing from 14 pairs of iCCA tumours and non-tumour liver tissues and propose S100P and SPP1 as markers for patient classification.