Type, Density, and Location of Immune Cells within Cholangiocarcinomas Predict Clinical Outcome

Abstract

Cholangiocarcinoma (CC) is a rare malignant tumor arising from bile duct cells. The prognosis of affected patients is poor. Several risk factors including cholangiolithiasis, liver fluke infection, and anatomical abnormalities, all associated with inflammation of the biliary tract, have been described. In addition, tumor-infiltrating immune cells (TIC) as well as expression of antigen presenting molecules are known to correlate with patient survival in several tumor entities. Therefore, we aimed to characterize the expression of major histocompatibility complex class I (MHC I) and TIC in a large cohort of CC (n=316) including extrahepatic (ECC) and intrahepatic (ICC) CC. TIC and MHC I-expression of tumor cells were assessed qualitatively and quantitatively by immunohistochemistry (CD4, CD8, CD20, CD68, and MHC I) using tissue microarrays. TIC and MHC I-expression were correlated with each other, clinicopathological variables, and patient survival. CC patients whose tumors displayed CD4+ and CD8+ TIC showed longer patient survival compared to patients without tumor associated inflammation (p=0.004, p=0.013, respectively). This result was also seen in the subgroup of ECC while in the subgroup of ICC CD4+ and CD8+ TIC were not able to predict patient survival. In CC, high MHC I-expression of tumor cells correlated significantly with a longer patient survival compared to CC with a low MHC I-expression of tumor cells (p=0.013). Additionally, high MHC I-expression in tumor cells was associated with increased levels of CD8+ (p=0.003) but not CD4+ or CD20+ TIC. Our findings indicate that tumoral expression of antigen presenting molecules and tumor associated inflammation might be of importance in the progression of CC and ultimately have an influence on the outcome of CC patients. However, our results also indicate that ECC and ICC might be different in this regard.