The Proximity of PD-1CD103 Tissue-Resident CD8 T Cells to Tumor Cells Is Correlated with Improved Clinical Outcomes in Patients with Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is characterized by a heterogeneous immune microenvironment, where the prognostic significance of CD8 tissue-resident memory T (T) cell activation and spatial positioning remains to be fully elucidated. This study investigated how the activation phenotypes and their spatial distribution relative to tumor cells influence anti-tumor immunosurveillance and predict clinical outcomes in CCA. Multiplex immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq) were employed to characterize naïve (PD-1CD103CD8) and exhausted (PD-1CD103CD8) subsets. G-cross function analysis was utilized to quantify the spatial proximity between these specific T subsets and tumor cells, correlating the spatial interaction with patient overall survival. scRNA-seq profiling revealed that PD-1CD103CD8 T cells were enriched in genes associated with lymphocyte activation and cytotoxicity, while PD-1CD103CD8 T cells exhibited an exhaustion signature. Spatially, PD-1CD103CD8 T cells exhibited increased interactions with tumor cells, whereas PD-1CD103CD8 T cells showed reduced engagement. Therefore, the close proximity of PD-1CD103CD8 T cells to tumor cells was identified as a significant predictor of favorable clinical outcomes. The activation state of CD8 T cells combined with their spatial localization constitutes a critical prognostic factor in CCA. Effective anti-tumor immunosurveillance relies on the direct engagement of naïve T cells with tumor cells. These findings highlight the potential of PD-1-targeted immunotherapies to remodel the spatial proximity of the tumor microenvironment, potentially promoting the redistribution of effector cells into tumor-proximal regions.