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Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.

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机构： [1]Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China [2]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China [3]Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China [4]School of Computer Science, Shanghai Key Laboratory of Intelligent Information Processing, Fudan University, Shanghai 200032, China [5]Department of Pathology, Shibei Hospital of Shanghai Jing’an District, Shanghai, 200435, China [6]Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China [7]The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China [8]Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai 200032, China [9]Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China [10]Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai 200540, China [11]State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China

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关键词： Cholangiocarcinoma Tumor microenvironment Tfh cells Treg cells Prognosis

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To investigate the prognostic value and relevant mechanisms of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA).We retrospectively included 962 patients from three cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples.A quaternary TLS scoring system was established for intra-tumor region (T score) and peri-tumor region (P score) respectively. T score positively correlated with favorable prognosis (P<0.001), whereas a high P score signified a worse survival (P<0.001). Then, mIHC demonstrated that both Tfh and Treg cells were significantly increased in intra-tumor TLSs than peri-tumor counterparts (P<0.05), and Treg cell frequencies within intra-tumor TLSs were positively associated with P score (P<0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into four Immune Classes with distinct prognosis (P<0.001) that differed in the abundance and distribution pattern of TLSs. Patients displayed an immune active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with immune excluded pattern survived at 5 years (P<0.001). The C-index of the Immune Class was statistically higher than the TNM staging system (0.73 vs 0.63, P<0.001). These results were validated in an internal and two external cohorts.The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. Tfh and Treg cells may play a critical role in determining the functional orientation of spatially different TLSs.Tertiary lymphoid structures (TLSs) have been attracting extensive attentions as they are associated with favorable prognosis through activating endogenous anti-tumor immune response. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains elusive. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed opposite prognostic impacts of TLSs located within or outside tumor region. The heterogeneous distribution of Tfh and Treg cells within the spatially different TLSs might be determinant of their functional state. Successfully, the integrated analysis of TLSs stratified iCCAs into four immune subclasses with distinct clinical outcomes.Copyright © 2021. Published by Elsevier B.V.

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出版当年[2022]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

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出版当年[2022]版：

Q1 GASTROENTEROLOGY & HEPATOLOGY

最新[2023]版：

Q1 GASTROENTEROLOGY & HEPATOLOGY

影响因子： 26.8 最新[2023版] 28 最新五年平均 25.7 出版当年[2022版] 26.2 出版当年五年平均 30.083 出版前一年[2021版] 26.8 出版后一年[2023版]

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第一作者机构： [1]Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China

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通讯作者：

通讯机构： [1]Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China [2]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China [3]Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China [9]Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China [10]Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai 200540, China [11]State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China [*1]Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital Fudan University, No.180, Feng Lin Road, Shanghai 200032, China. [*2]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China. [*3]Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, No.37 Guoxue Road, Chengdu 610041, China.

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Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.