TY - JOUR
T1 - Spatiotemporal analysis of tumour-infiltrating immune cells in biliary carcinogenesis
AU - Charbel, Alphonse
AU - Tavernar, Luca
AU - Albrecht, Thomas
AU - Brinkmann, Fritz
AU - Verheij, Joanne
AU - Roos, Eva
AU - Vogel, Monika Nadja
AU - Köhler, Bruno
AU - Springfeld, Christoph
AU - Brobeil, Alexander
AU - Schirmacher, Peter
AU - Singer, Stephan
AU - Mehrabi, Arianeb
AU - Roessler, Stephanie
AU - Goeppert, Benjamin
N1 - Funding Information: This work was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 314905040 – SFB/TRR 209 Liver Cancer (B01 to SR and Z01, INF to PS). This study was in part supported by funds from the PSC Partners Seeking A Cure Foundation USA to BG and SR. Open Access funding enabled and organized by Projekt DEAL. Funding Information: We are grateful to Veronika Geißler, Nina Wilhelm and Carolin Kerber (Tissue Bank of the National Centre for Tumour Diseases (NCT) Heidelberg, Germany, and Institute of Pathology Heidelberg) for excellent technical assistance. Tissue samples were provided by the tissue bank of the National Centre for Tumour Diseases (NCT; Heidelberg, Germany) in accordance with the regulations of the tissue bank and with the approval of the Ethics Committee of Heidelberg University (S-519/2019). Parts of Fig. 1 were created with BioRender.com. Publisher Copyright: © 2022, The Author(s).
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Background: Intraductal papillary neoplasms (IPN) and biliary epithelial neoplasia (BilIN) are well‐defined precursor lesions of biliary tract carcinoma (BTC). The aim of this study was to provide a comprehensive characterisation of the inflammatory microenvironment in BTC precursor lesions. Methods: Immunohistochemistry was employed to assess tumour-infiltrating immune cells in tissue samples from patients, for whom precursor lesions were identified alongside invasive BTC. The spatiotemporal evolution of the immune microenvironment during IPN-associated carcinogenesis was comprehensively analysed using triplet sample sets of non-neoplastic epithelium, precursor lesion and invasive BTC. Immune-cell dynamics during IPN- and BilIN-associated carcinogenesis were subsequently compared. Results: Stromal CD3 + (P = 0.002), CD4 + (P = 0.007) and CD8 + (P < 0.001) T cells, CD20 + B cells (P = 0.008), MUM1 + plasma cells (P = 0.012) and CD163 + M2-like macrophages (P = 0.008) significantly decreased in IPN compared to non-tumorous biliary epithelium. Upon transition from IPN to invasive BTC, stromal CD68 + (P = 0.001) and CD163 + (P < 0.001) macrophages significantly increased. In contrast, BilIN-driven carcinogenesis was characterised by significant reduction of intraepithelial CD8 + T-lymphocytic infiltration from non-tumorous epithelium via BilIN (P = 0.008) to BTC (P = 0.004). Conclusion: IPN and BilIN are immunologically distinct entities that undergo different immune-cell variations during biliary carcinogenesis. Intraepithelial CD8 + T-lymphocytic infiltration of biliary tissue decreased already at the IPN-precursor stage, whereas BilIN-associated carcinogenesis showed a slowly progressing reduction towards invasive carcinoma.
AB - Background: Intraductal papillary neoplasms (IPN) and biliary epithelial neoplasia (BilIN) are well‐defined precursor lesions of biliary tract carcinoma (BTC). The aim of this study was to provide a comprehensive characterisation of the inflammatory microenvironment in BTC precursor lesions. Methods: Immunohistochemistry was employed to assess tumour-infiltrating immune cells in tissue samples from patients, for whom precursor lesions were identified alongside invasive BTC. The spatiotemporal evolution of the immune microenvironment during IPN-associated carcinogenesis was comprehensively analysed using triplet sample sets of non-neoplastic epithelium, precursor lesion and invasive BTC. Immune-cell dynamics during IPN- and BilIN-associated carcinogenesis were subsequently compared. Results: Stromal CD3 + (P = 0.002), CD4 + (P = 0.007) and CD8 + (P < 0.001) T cells, CD20 + B cells (P = 0.008), MUM1 + plasma cells (P = 0.012) and CD163 + M2-like macrophages (P = 0.008) significantly decreased in IPN compared to non-tumorous biliary epithelium. Upon transition from IPN to invasive BTC, stromal CD68 + (P = 0.001) and CD163 + (P < 0.001) macrophages significantly increased. In contrast, BilIN-driven carcinogenesis was characterised by significant reduction of intraepithelial CD8 + T-lymphocytic infiltration from non-tumorous epithelium via BilIN (P = 0.008) to BTC (P = 0.004). Conclusion: IPN and BilIN are immunologically distinct entities that undergo different immune-cell variations during biliary carcinogenesis. Intraepithelial CD8 + T-lymphocytic infiltration of biliary tissue decreased already at the IPN-precursor stage, whereas BilIN-associated carcinogenesis showed a slowly progressing reduction towards invasive carcinoma.
KW - Bile Duct Neoplasms/pathology
KW - Bile Ducts, Intrahepatic/pathology
KW - Bile Pigments
KW - Biliary Tract Neoplasms/pathology
KW - Biliary Tract/pathology
KW - Carcinogenesis/pathology
KW - Cholangiocarcinoma/pathology
KW - Humans
KW - Spatio-Temporal Analysis
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85137770429&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41416-022-01933-0
DO - https://doi.org/10.1038/s41416-022-01933-0
M3 - Article
C2 - 36068277
SN - 0007-0920
VL - 127
SP - 1603
EP - 1614
JO - British journal of cancer
JF - British journal of cancer
IS - 9
ER -