目的:小型(SD-iCCA)和大型(LD-iCCA)导管型肝内胆管癌的专用基因特征仍然未知。我们在SD-和LD-iCCA中进行了免疫分析,以确定用于个性化医疗的新型生物标志物候选物。
方法:回顾,19例SD-iCCA患者(n=10,中位年龄,63.1岁(45-86岁);男性,4)或LD-iCCA(n=9,中位年龄,69.7岁(62-85岁);男性,5))包括在内。所有患者均在2009年4月至2021年1月之间进行诊断和组织学确认。使用NanoStringnCounter®PanCancer免疫分析面板处理肿瘤组织样品以进行差异表达分析。
结果:除补码签名外,免疫相关途径在SD-iCCA与LD-iCCA.在DMBT1(log2fc=-5.39,p=0.01)和CEACAM6(log2fc=-6.38,p=0.01)的SD-iCCA中共有20个免疫相关基因强烈下调,表现出最强的下调。在7个强烈上调的基因(log2fc>2,p≤0.02)中,CRP(log2fc=5.06,p=0.02)排名第一,另外四个与补体相关(C5,C4BPA,C8A,C8B).总肿瘤浸润淋巴细胞(TIL)特征在SD-iCCA中减少,耗竭的CD8/TIL比率升高,NK/TIL,和细胞毒性细胞/TIL,而B细胞/TIL的比率降低,肥大细胞/TIL和树突状细胞/TIL。SD-iCCA中的免疫谱分析特征揭示了趋化因子信号传导途径的下调,包括JAK2/3和ERK1/2以及几乎所有细胞因子-细胞因子受体相互作用途径,CXCL1/CXCR1轴除外。
结论:SD-iCCA与LD-iCCA的免疫模式不同。我们确定了潜在的生物标志物候选基因,包括CRP,CEACAM6,DMBT1和可用于增强诊断和治疗决策的各种补体因子。
OBJECTIVE: 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.
CONCLUSIONS: 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.