The Transmembrane Receptor TIRC7 Identifies a Distinct Subset of Immune Cells with Prognostic Implications in Cholangiocarcinoma

SIMPLE SUMMARY: Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis due to rapid tumoral spread and poor therapeutic options. Innovative therapies, such as immune-modulating drugs, are urgently needed. Here, we assessed the quantity and clinical implications of immune cells expressing the T cell immune response cDNA 7 receptor (TIRC7) in a cohort of 135 CCA patients. We found that TIRC7(+) immune cells are present both in the tumor epithelia and in the stroma in the majority of patients with particularly high intraepithelial levels in intrahepatic CCA. Distinct histomorphological tumor subtypes were exclusively associated with a TIRC7(+) phenotype. By correlation analysis, we uncovered that a high level of intraepithelial TIRC7(+) immune cells was associated with a favorable prognosis in intrahepatic CCA. Our results reveal a distinct subset of immune cells marked by TIRC7 to be present and prognostically relevant in CCA. ABSTRACT: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with a dismal prognosis. Therapeutic options are largely limited to surgery and conventional chemotherapy offers limited benefit. As immunotherapy has proven highly effective in various cancer types, we have undertaken a quantitative immunohistopathological assessment of immune cells expressing the immunoinhibitory T cell immune response cDNA 7 receptor (TIRC7), an emerging immunoinhibitory receptor, in a cohort of 135 CCA patients. TIRC7(+) immune cells were present in both the tumor epithelia and stroma in the majority of CCA cases with the highest levels found in intrahepatic CCA. While intraepithelial density of TIRC7(+) immune cells was decreased compared to matched non-neoplastic bile ducts, stromal quantity was higher in the tumor samples. Tumors exhibiting signet ring cell or adenosquamous morphology were exclusively associated with an intraepithelial TIRC7(+) phenotype. Survival analysis showed intraepithelial TIRC7(+) immune cell density to be a highly significant favorable prognosticator in intrahepatic but not proximal or distal CCA. Furthermore, intraepithelial TIRC7(+) immune cell density correlated with the number of intraepithelial CD8(+) immune cells and with the total number of CD4(+) immune cells. Our results suggest the presence and prognostic relevance of TIRC7(+) immune cells in CCA and warrant further functional studies on its pharmacological modulation.