Immune and Histopathological Biomarkers for Prognosis and Neoadjuvant Immunotherapy Response in Intrahepatic...

The tumor microenvironment (TME) plays a critical role in determining the clinical outcomes in patients with intrahepatic cholangiocarcinoma (iCCA). This study investigates the prognostic significance of CD8+ T cells and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs) and their relationship to histopathological features.

Immunofluorescence analysis was conducted on a cohort of 34 resected iCCA cases to assess CD8+ T cell and Treg densities. Statistical correlations with survival and immune and histopathological features were examined. Validation was performed on an independent cohort of 95 iCCA pre-neoadjuvant therapy (NAT) biopsy specimens to assess the prognostic power of the immune and histopathological features to survival and NAT response.

In the cohort of resected iCCA cases, immunofluorescence revealed that increased CD8+ T-cell infiltration is associated with improved survival (p = 0.018), underscoring their role in anti-tumor immunity. Conversely, higher density of Tregs is linked to poorer survival (p = 0.038), suggesting its tumor-promoting, immunosuppressive effects. Intriguingly, CD8+ T cells and Tregs are associated with distinct histopathological features, with CD8+ T cells correlating with dense tumor-infiltrating lymphocytes (TILs, Pearson's R = 0.498; p = 0.004) and Tregs being more prevalent in regions of tumor budding (TB, Pearson's R = 0.382; p = 0.029). These observations were validated in an independent pre-NAT cohort (n = 95), whereby higher TIL density, particularly increased CD8+ T cells and reduced Treg, and lower TB predict favorable response to NAT, as shown by improved overall and disease-free survival.

These findings provide critical insights for stratifying patients and highlight the potential for optimizing immune-targeted therapies in patients with iCCA.