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

Thomas Albrecht; Benjamin Goeppert; Fritz Brinkmann; Alphonse Charbel; Qiangnu Zhang; Johannes Schreck; Nina Wilhelm; Stephan Singer; Bruno C Köhler; Christoph Springfeld; Arianeb Mehrabi; Peter Schirmacher; Anja A Kühl; Monika N Vogel; Holger Jansen; Nalân Utku; Stephanie Roessler

doi:10.3390/cancers13246272

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

Cancers (Basel). 2021 Dec 14;13(24):6272. doi: 10.3390/cancers13246272.

Authors

Thomas Albrecht^{1

2}, Benjamin Goeppert^{1

2}, Fritz Brinkmann^{1

2}, Alphonse Charbel^{1

2}, Qiangnu Zhang^{1

2}, Johannes Schreck^{1

2}, Nina Wilhelm³, Stephan Singer⁴, Bruno C Köhler^{2

5}, Christoph Springfeld^{2

5}, Arianeb Mehrabi^{2

6}, Peter Schirmacher^{1

2}, Anja A Kühl⁷, Monika N Vogel⁸, Holger Jansen⁹, Nalân Utku⁹, Stephanie Roessler^{1

2}

Affiliations

¹ Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
² Liver Cancer Center Heidelberg (LCCH), 69120 Heidelberg, Germany.
³ Tissue Bank of the National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁴ Institute of Pathology and Neuropathology, Eberhard-Karls University, 72076 Tübingen, Germany.
⁵ Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁶ Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁷ Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, iPATH.Berlin, 12203 Berlin, Germany.
⁸ Diagnostic and Interventional Radiology, Thoraxklinik at Heidelberg University Hospital, 69126 Heidelberg, Germany.
⁹ Institute for Medical Immunology, Campus Virchow, Charité, Augustenburger Platz 1, 13353 Berlin, Germany.

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.

Keywords: PD-L1; TIRC7; biomarkers; cholangiocarcinoma; immune checkpoint inhibitors; immunotherapy; tumor microenvironment.

Abstract

Grants and funding