Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma

Isis Lozzi; Alexander Arnold; Matthias Barone; Juliette Claire Johnson; Bruno V Sinn; Johannes Eschrich; Pimrapat Gebert; Ruonan Wang; Mengwen Hu; Linda Feldbrügge; Anja Schirmeier; Anja Reutzel-Selke; Thomas Malinka; Felix Krenzien; Wenzel Schöning; Dominik P Modest; Johann Pratschke; Igor M Sauer; Matthäus Felsenstein

doi:10.1080/2162402X.2024.2406052

OncoImmunology (Dec 2024)

Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma

Isis Lozzi,
Alexander Arnold,
Matthias Barone,
Juliette Claire Johnson,
Bruno V Sinn,
Johannes Eschrich,
Pimrapat Gebert,
Ruonan Wang,
Mengwen Hu,
Linda Feldbrügge,
Anja Schirmeier,
Anja Reutzel-Selke,
Thomas Malinka,
Felix Krenzien,
Wenzel Schöning,
Dominik P Modest,
Johann Pratschke,
Igor M Sauer,
Matthäus Felsenstein

Affiliations

Isis Lozzi: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Alexander Arnold: Department of Pathology, CCM, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Matthias Barone: Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
Juliette Claire Johnson: Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
Bruno V Sinn: Department of Pathology, CCM, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Johannes Eschrich: Department of Hepatology and Gastroenterology, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
Pimrapat Gebert: Institute of Biometry and Clinical Epidemiology, CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Ruonan Wang: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Mengwen Hu: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Linda Feldbrügge: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Anja Schirmeier: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Anja Reutzel-Selke: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Thomas Malinka: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Felix Krenzien: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Wenzel Schöning: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Dominik P Modest: Department of Hematology, Oncology, and Cancer Immunology, CCM, CVK, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
Johann Pratschke: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Igor M Sauer: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Matthäus Felsenstein: Department of Surgery, Experimental Surgery, CCM, CVK, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

DOI: https://doi.org/10.1080/2162402X.2024.2406052
Journal volume & issue: Vol. 13, no. 1

Abstract

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Background Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.Methods Liver tissue samples were collected during 2008–2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53).Results CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells (“hot” cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.Conclusions These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with “hot” TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn “cold” into “hot” TIME in ICC.

Published in OncoImmunology

ISSN: 2162-402X (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy; Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.tandfonline.com/journals/koni

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