Mapping of the T Cell Landscape of Biliary Tract Cancer Unravels Anatomical Subtype-Specific Heterogeneity

IF 12.5 1区 医学 Q1 ONCOLOGY
Jianhua Nie, Shuyuan Zhang, Ying Guo, Caiqi Liu, Jiaqi Shi, Haotian Wu, Ruisi Na, Yingjian Liang, Shan Yu, Fei Quan, Kun Liu, Mingwei Li, Meng Zhou, Ying Zhao, Xuehan Li, Shengnan Luo, Qian Zhang, Guangyu Wang, Yanqiao Zhang, Yuanfei Yao, Yun Xiao, Sheng Tai, Tongsen Zheng
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引用次数: 0

Abstract

Biliary tract cancer (BTC), encompassing diseases such as intrahepatic (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), is not only on the rise but also poses a significant and urgent health threat due to its high malignancy. Genomic differences point to the possibility that these subtypes represent distinct diseases. Elucidation of the specific distribution of T cell subsets, critical to cancer immunity, across these diseases could provide better insights into the unique biology of BTC subtypes and help identify potential precision medicine strategies. To address this, we conducted scRNA-seq and scTCR-seq on CD3+ T cells from 36 samples from 16 BTC patients across all subtypes and analyzed 355 pathological slides to examine the spatial distribution of T cells and tertiary lymphoid structures (TLS). Compared to ICC and GBC, ECC possessed a unique immune profile characterized by T cell exhaustion, elevated CXCL13 expression in CD4+ T helper-like and CD8+CXCL13+ exhausted T cells, more mature TLS, and fewer desert immunophenotypes. Conversely, ICC displayed an inflamed immunophenotype with an enrichment of interferon related pathways and high expression of LGALS1 in activated regulatory T cells, associated with immunosuppression. Inhibition of LGALS1 reduced tumor growth and Treg prevalence in ICC mouse models. Overall, this study unveils T cell diversity across BTC subtypes at the single-cell and spatial level that could open paths for tailored immunotherapies.
胆道癌 T 细胞图谱揭示了解剖亚型特异性异质性
胆道癌(BTC)包括肝内胆管癌(ICC)、肝外胆管癌(ECC)和胆囊癌(GBC)等疾病,不仅发病率呈上升趋势,而且因其恶性程度高而对健康构成重大而紧迫的威胁。基因组差异表明,这些亚型可能代表不同的疾病。阐明对癌症免疫至关重要的 T 细胞亚群在这些疾病中的具体分布,可以更好地了解 BTC 亚型的独特生物学特性,并有助于确定潜在的精准医疗策略。为此,我们对来自16名BTC患者的36份样本中的CD3+ T细胞进行了scRNA-seq和scTCR-seq分析,这些样本来自所有亚型,我们还分析了355张病理切片,以研究T细胞和三级淋巴结构(TLS)的空间分布。与 ICC 和 GBC 相比,ECC 具有独特的免疫特征,其特点是 T 细胞衰竭、CD4+ T 辅助细胞样和 CD8+CXCL13+ 衰竭 T 细胞中 CXCL13 表达升高、TLS 更成熟、沙漠免疫表型更少。相反,ICC 显示出炎症免疫表型,干扰素相关通路丰富,活化的调节性 T 细胞中 LGALS1 高表达,这与免疫抑制有关。抑制 LGALS1 可减少 ICC 小鼠模型中的肿瘤生长和 Treg 的流行。总之,这项研究在单细胞和空间水平上揭示了BTC亚型中T细胞的多样性,为定制免疫疗法开辟了道路。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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