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Abstract：
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.
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.
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).
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.
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.
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).
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.
摘要：
导管内乳头状肿瘤（IPN）和胆管上皮瘤（BilIN）是明确定义的胆道癌（BTC）的前体病变。这项研究的目的是提供BTC前体病变中炎症微环境的全面表征。
免疫组织化学用于评估患者组织样本中的肿瘤浸润免疫细胞，与侵袭性BTC同时发现的前体病变。使用非肿瘤上皮的三联体样品集全面分析了IPN相关癌变过程中免疫微环境的时空演变，前兆病变和侵入性BTC。随后比较了IPN-和BilIN相关癌变过程中的免疫细胞动力学。
基质型CD3+(P=0.002),CD4+（P=0.007）和CD8+（P<0.001）T细胞，CD20+B细胞（P=0.008），与非肿瘤胆管上皮相比，IPN中的MUM1浆细胞（P=0.012）和CD163M2样巨噬细胞（P=0.008）显着降低。从IPN过渡到侵入性BTC后，基质中CD68+(P=0.001)和CD163+(P<0.001)巨噬细胞显著增多。相比之下,BilIN驱动的致癌作用的特征是通过BilIN（P=0.008）到BTC（P=0.004），上皮内CD8T淋巴细胞从非肿瘤上皮浸润显着减少。
IPN和BilIN是免疫学上不同的实体，在胆道癌变过程中经历不同的免疫细胞变异。胆道组织的上皮内CD8+T淋巴细胞浸润在IPN前体阶段已经减少，而BilIN相关癌变显示向浸润性癌缓慢进展。
免疫组织化学用于评估患者组织样本中的肿瘤浸润免疫细胞，与侵袭性BTC同时发现的前体病变。使用非肿瘤上皮的三联体样品集全面分析了IPN相关癌变过程中免疫微环境的时空演变，前兆病变和侵入性BTC。随后比较了IPN-和BilIN相关癌变过程中的免疫细胞动力学。
基质型CD3+(P=0.002),CD4+（P=0.007）和CD8+（P<0.001）T细胞，CD20+B细胞（P=0.008），与非肿瘤胆管上皮相比，IPN中的MUM1浆细胞（P=0.012）和CD163M2样巨噬细胞（P=0.008）显着降低。从IPN过渡到侵入性BTC后，基质中CD68+(P=0.001)和CD163+(P<0.001)巨噬细胞显著增多。相比之下,BilIN驱动的致癌作用的特征是通过BilIN（P=0.008）到BTC（P=0.004），上皮内CD8T淋巴细胞从非肿瘤上皮浸润显着减少。
IPN和BilIN是免疫学上不同的实体，在胆道癌变过程中经历不同的免疫细胞变异。胆道组织的上皮内CD8+T淋巴细胞浸润在IPN前体阶段已经减少，而BilIN相关癌变显示向浸润性癌缓慢进展。
