Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
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Published:2024-01-20
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Lu Jia-ChengORCID, Wu Lei-Lei, Sun Yi-Ning, Huang Xiao-Yong, Gao Chao, Guo Xiao-Jun, Zeng Hai-Ying, Qu Xu-Dong, Chen Yi, Wu Dong, Pei Yan-Zi, Meng Xian-Long, Zheng Yi-Min, Liang Chen, Zhang Peng-Fei, Cai Jia-Bin, Ding Zhen-Bin, Yang Guo-Huan, Ren Ning, Huang Cheng, Wang Xiao-Ying, Gao Qiang, Sun Qi-Man, Shi Ying-Hong, Qiu Shuang-Jian, Ke Ai-Wu, Shi Guo-MingORCID, Zhou JianORCID, Sun Yi-DiORCID, Fan JiaORCID
Abstract
AbstractIntratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+–CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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