Hepatology communications
Genomic and immune profiling characterizes immune heterogeneity and a TIGIT-associated subtype in intrahepatic cholangiocarcinoma
By Korosteleva A, Reschke JS, Yi D and 14 others.
Abstract
Background
Intrahepatic cholangiocarcinoma (iCCA) is characterized by marked molecular and microenvironmental heterogeneity and moderate response to immunotherapy. We aimed to define the genomic and spatial determinants of immune checkpoint activity in iCCA and their association with clinical outcome.
Methods
We performed integrated transcriptomic, DNA panel sequencing, and multiplex immunohistochemistry analyses in a cohort of 144 patients with iCCA. Tumors were classified according to STIM-defined microenvironmental subtypes. Spatially resolved immune profiling was conducted across the tumor core, stroma, invasive margin, and adjacent liver. Immune checkpoint expression, cellular proximity, and clinical outcome were analyzed using Cox regression and Kaplan-Meier methods. TIGIThigh tumors were further characterized by differential gene expression and pathway enrichment analyses.ResultsSTIM classification stratified tumors into inflamed (47%) and non-inflamed (53%) subtypes with distinct survival outcomes and genomic profiles. Recurrent alterations in CDKN2A/B, TP53, MTAP, and BAP1 showed subtype-specific enrichment and prognostic relevance. Spatial immune profiling revealed compartment-specific distributions of T cells and immune checkpoints, with predominance of TIGIT and PD-1 expression in stromal and marginal regions. Most tumor-infiltrating T cells lacked inhibitory receptor expression, while co-expression of multiple checkpoints was uncommon. TIGIThigh tumors displayed coordinated activation of immune effector, antigen presentation, and interferon signaling pathways, alongside enrichment of distinct genomic alterations, defining an immune-activated molecular subtype.