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. 2024 Jul 22;150(7):357.
doi: 10.1007/s00432-024-05888-y.

Small duct and large duct type intrahepatic cholangiocarcinoma reveal distinct patterns of immune signatures

Simon Bernatz  1   2   3   4 , Falko Schulze  2 , Julia Bein  2 , Katrin Bankov  2   5 , Scherwin Mahmoudi  1 , Leon D Grünewald  1 , Vitali Koch  1 , Angelika Stehle  6 , Andreas A Schnitzbauer  7 , Dirk Walter  6 , Fabian Finkelmeier  3   6 , Stefan Zeuzem  6 , Thomas J Vogl  1 , Peter J Wild  2   3   8 , Maximilian N Kinzler  9
Affiliations

Small duct and large duct type intrahepatic cholangiocarcinoma reveal distinct patterns of immune signatures

Simon Bernatz et al. J Cancer Res Clin Oncol. .

Abstract

Purpose: Dedicated gene signatures in small (SD-iCCA) and large (LD-iCCA) duct type intrahepatic cholangiocarcinoma remain unknown. We performed immune profiling in SD- and LD-iCCA to identify novel biomarker candidates for personalized medicine.

Methods: Retrospectively, 19 iCCA patients with either SD-iCCA (n = 10, median age, 63.1 years (45-86); men, 4) or LD-iCCA (n = 9, median age, 69.7 years (62-85); men, 5)) were included. All patients were diagnosed and histologically confirmed between 04/2009 and 01/2021. Tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer Immune Profiling Panel.

Results: With the exception of complement signatures, immune-related pathways were broadly downregulated in SD-iCCA vs. LD-iCCA. A total of 20 immune-related genes were strongly downregulated in SD-iCCA with DMBT1 (log2fc = -5.39, p = 0.01) and CEACAM6 (log2fc = -6.38, p = 0.01) showing the strongest downregulation. Among 7 strongly (log2fc > 2, p ≤ 0.02) upregulated genes, CRP (log2fc = 5.06, p = 0.02) ranked first, and four others were associated with complement (C5, C4BPA, C8A, C8B). Total tumor-infiltrating lymphocytes (TIL) signature was decreased in SD-iCCA with elevated ratios of exhausted-CD8/TILs, NK/TILs, and cytotoxic cells/TILs while having decreased ratios of B-cells/TILs, mast cells/TILs and dendritic cells/TILs. The immune profiling signatures in SD-iCCA revealed downregulation in chemokine signaling pathways inclulding JAK2/3 and ERK1/2 as well as nearly all cytokine-cytokine receptor interaction pathways with the exception of the CXCL1/CXCR1-axis.

Conclusion: Immune patterns differed in SD-iCCA versus LD-iCCA. We identified potential biomarker candidate genes, including CRP, CEACAM6, DMBT1, and various complement factors that could be explored for augmented diagnostics and treatment decision-making.

Keywords: Biomarker; Cholangiocarcinoma; Immune profiling; Intrahepatic; Pathology, molecular; Surgical oncology.

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Conflict of interest statement

F. F. has received travel support from Ipsen, Abbvie, Astrazeneca and speaker’s fees from AbbVie, MSD, Ipsen, Astra. S.Z. has received speaker fees and/or honoraria for consultancy from Abbvie, BioMarin, Gilead, Intercept, Janssen, Madrigal, MSD/Merck, NovoNordisk, SoBi and Theratechnologies. P.J.W. has received consulting fees and honoraria for lectures by Bayer, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx, and Astra Zeneca; research support was provided by Astra Zeneca. The authors declare that there is no relationship relevant to the manuscripts’ subject. All other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
STARD Flowchart of patient inclusion into the study. STARD Standards for Reporting Diagnostic Accuracy Studies
Fig. 2
Fig. 2
Dominant downregulation in immune pathway scores in small-duct type intrahepatic cholangiocarcinoma. a T-SNE plot of comprehensive log2 normalized mRNA patient data, b trend plot of pathway signatures using NanoString® pathway score analysis tool and c boxplots of the top 4 differentially expressed pathway score signatures
Fig. 3
Fig. 3
Differentially expressed genes between intrahepatic cholangiocarcinoma subtypes. a Volcano plot of all differentially expressed genes and only b strong and significantly (log2fc < -2 or > 2 and p-value < 0.05 with Benjamini–Hochberg correction)
Fig. 4
Fig. 4
Cell type profiling revealed decreased immune infiltrates in SD-iCCA. Cell population abundance was measured based on characteristically expressed genes. The cell type abundance measurements are plotted against the tumor subtypes. a Total cell type scores and b the relative cell type scores. c, d Top differentially expressed cell type scores relative to total TILs c with downregulation in small-duct type iCCA or d upregulation in SD-iCCA
See this image and copyright information in PMC

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