Enhanced ICOS Signaling Between Dendritic Cells and T Cells Characterizes the Immune Landscape of Human Cholangiocarcinoma

Abstract

Cholangiocarcinoma exhibits a complex tumor microenvironment, yet the cellular interactions governing its progression remain poorly understood. Here, through integrated analysis of two independent single-cell RNA sequencing datasets comprising both complete tissue and immune-focused profiling, we comprehensively mapped the cellular landscape and intercellular communication networks in human cholangiocarcinoma. Our analysis revealed significant remodeling of immune cell compositions and interaction patterns in the tumor microenvironment. Notably, we identified enhanced ICOS signaling between dendritic cells and T cells as a prominent feature of cholangiocarcinoma. Using CellChat analysis, we demonstrated that tumor-associated dendritic cells, particularly plasmacytoid DCs, exhibit stronger ICOS-mediated communication with T cells compared to their counterparts in normal tissues. Functional validation experiments confirmed that tumor-conditioned dendritic cells upregulate ICOSL expression and promote CD8+ T-cell activation through the ICOS–ICOSL axis, as evidenced by increased CD69 and CD25 expression. This activation was specifically abolished by ICOSL blockade, establishing the functional significance of this pathway. Our findings provide novel insights into tumor-immune interactions in cholangiocarcinoma and suggest the ICOS–ICOSL axis as a potential therapeutic target for immunotherapy.