Correlation of Vein-Rich Tumor Microenvironment of Intrahepatic Cholangiocarcinoma With Tertiary Lymphoid Structures and Patient Outcome

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer composed of large-duct and small-duct types. Understanding the tumor immune microenvironment and its related vascular system is important for developing novel and efficient therapies. We focused on tertiary lymphoid structure (TLS) as a hallmark of antitumor immunity and investigated the clinicopathologic significance of TLSs and the influence of vascular microenvironment on TLS formation in iCCAs. We examined 261 iCCA cases clinicopathologically and analyzed the vascular system using immunohistochemistry. Single-cell (102,685 cells) and bulk RNA (33 iCCA cases) sequencing analyses were performed using data sets downloaded from public databases, and endothelial cell characteristics in iCCA tissues and functional networks related to the tumor microenvironment were bioinformatically examined. High densities of both intratumoral and peritumoral TLSs were significantly associated with prolonged survival only in large-duct-type iCCA. Multivariate analyses showed that peritumoral TLS was a prognostic factor for the large-duct type. TLS-rich iCCA had a significantly higher vein density and tumor-infiltrating T-cell count than TLS-poor iCCA. Both the presence of TLSs and high vein endothelial cells in iCCA tissues were significantly associated with molecular networks representing active immune responses in transcriptomic analysis. Vein density was a prognostic factor in patients with large-duct and small-duct types. This suggests that TLS formation is involved in a microenvironment with high vein density, which represents an antitumor-directed immune microenvironment.