PO.CL12.02 · 临床研究
整合多组学分析鉴定出胆管癌中一种免疫治疗易感且与预后相关的亚型
Integrated multi-omics profiling identifies an immunotherapy vulnerable and prognostic associated subtype in cholangiocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胆管癌（CCA）是一种侵袭性恶性肿瘤，预后差，治疗选择有限。本研究对424例CCA患者进行了整合多组学分析及免疫组化验证，鉴定出四种具有不同临床和免疫学特征的分子亚型：C1（增殖型）：由*TP53/KRAS*突变和CpG岛甲基化表型（CIMP+）高甲基化驱动，表现为Th17细胞浸润和预后不良；C2（免疫抑制型Macro_LYVE1，（ISM_LYVE1））：富含基质，伴LYVE1⁺巨噬细胞和上皮-间质转化（EMT）激活；C3（免疫激活型Macro_C1QC（ISM_C1QC））：富集C1QC⁺巨噬细胞、CD8⁺T细胞及代谢通路，对免疫检查点阻断高度反应（总缓解率（ORR）75%）；C4（免疫排斥型（IE））：FGFR2改变和IDH1突变，呈免疫“冷”表型。我们验证了ATP2B1作为一种新的预后生物标志物，并开发了一个用于亚型预测的160基因分类器。C3亚型对免疫检查点阻断（ICB）的卓越反应独立于传统生物标志物（PD-L1/微卫星不稳定性（MSI）/肿瘤突变负荷（TMB）），凸显了该分类系统在指导CCA精准免疫治疗中的临床应用价值。
查看英文原文 English abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy with poor prognosis and limited treatment options. This study performed integrated multi-omics profiling as well as immunohistochemical validation on 424 CCA patients, identifying four molecular subtypes with distinct clinical and immunological features: C1 (Proliferative): Driven by *TP53/KRAS* mutations and CpG island methylator phenotype (CIMP+) hypermethylation, showing Th17 cells infiltration and poor outcomes; C2 (Immune-Suppressed Macro_LYVE1, (ISM_LYVE1)): Stroma-rich with LYVE1⁺ macrophages and epithelial-mesenchymal transition (EMT) activation; C3 (Immune-Activated Macro_C1QC (ISM_C1QC)): Enriched in C1QC⁺ macrophages, CD8⁺ T-cells, and metabolic pathways, highly responsive to immune checkpoint blockade (75% Overall Response Rate (ORR)); C4 (Immune-Excluded, (IE)): FGFR2-altered and IDH1-mutant, with an immunologically-cold phenotype. We validated ATP2B1 as a novel prognostic biomarker and developed a 160-gene classifier for subtype prediction. The C3 subtype's exceptional immune checkpoint blockade (ICB) response, independent of conventional biomarkers (PD-L1/microsatellite instability (MSI)/tumor mutational burden (TMB)), highlights the clinical utility of this classification system in guiding precision immunotherapy for CCA.
利益披露 Disclosure
L. Chen, None..
X. Tian, None.