The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome

BACKGROUND: This study aimed to investigate the clinical relevance of the immune microenvironment in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC‐ICC). PATIENTS AND METHODS: The density of tumor‐infiltrating CD3(+), CD8(+), CD163(+), and Foxp3(+) immune cells, as well as Programmed cell death 1, Programmed cell death‐ligand 1, and Tumor necrosis factor receptor superfamily member 4, was measured in the peritumor liver, tumor invasive margin, and intratumor subregions of 56 cHCC‐ICC by immunohistochemistry. The immune index was established to stratify patients. Prognostic significance of immune cell subsets and immune indices was evaluated. RESULTS: The distribution of immune cells was highly heterogeneous among different subregions of cHCC‐ICC. As compared with the hepatocellular carcinoma (HCC) component, the lower density of CD8(+) T cells and higher intensity of Foxp3(+) Tregs and immune checkpoints in the intrahepatic cholangiocarcinoma (ICC) component may indicate a stronger immune evasive ability of ICC. Based on clustering classification or a combination of random forest and lasso‐cox, two models of immune indices were established and both were identified as independent prognostic factors for cHCC‐ICC patients. The selected immune variables in the immune prognostic models derived from both HCC and ICC subregions, indicating that the prognosis of cHCC‐ICC patients was a complex interaction of both components. CONCLUSIONS: The immune contexture was heterogeneous among different subregions of cHCC‐ICC patients and contributed differently to patient prognosis. Immune score based on the densities of immune cells might serve as a promising prognostic predictor for cHCC‐ICC patients.