Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma

Jia-Cheng Lu, Lei-Lei Wu, Yi-Ning Sun, Xiao-Yong Huang, Chao Gao, Xiao-Jun Guo, Hai-Ying Zeng, Xu-Dong Qu, Yi Chen, Dong Wu, Yan-Zi Pei, Xian-Long Meng, Yi-Min Zheng, Chen Liang, Peng-Fei Zhang, Jia-Bin Cai, Zhen-Bin Ding, Guo-Huan Yang, Ning Ren, Cheng Huang, Xiao-Ying Wang, Qiang Gao, Qi-Man Sun, Ying-Hong Shi, Shuang-Jian Qiu, Ai-Wu Ke, Guo-Ming Shi (), Jian Zhou (), Yi-Di Sun () and Jia Fan ()
Additional contact information
Jia-Cheng Lu: Fudan University
Lei-Lei Wu: Chinese Academy of Sciences
Yi-Ning Sun: Chinese Academy of Sciences
Xiao-Yong Huang: Fudan University
Chao Gao: Fudan University
Xiao-Jun Guo: Fudan University
Hai-Ying Zeng: Fudan University
Xu-Dong Qu: Fudan University
Yi Chen: Fudan University
Dong Wu: Fudan University
Yan-Zi Pei: Fudan University
Xian-Long Meng: Fudan University
Yi-Min Zheng: Fudan University
Chen Liang: Fudan University
Peng-Fei Zhang: Ministry of Education of the People’s Republic of China
Jia-Bin Cai: Fudan University
Zhen-Bin Ding: Fudan University
Guo-Huan Yang: Fudan University
Ning Ren: Fudan University
Cheng Huang: Fudan University
Xiao-Ying Wang: Fudan University
Qiang Gao: Fudan University
Qi-Man Sun: Fudan University
Ying-Hong Shi: Fudan University
Shuang-Jian Qiu: Fudan University
Ai-Wu Ke: Fudan University
Guo-Ming Shi: Fudan University
Jian Zhou: Fudan University
Yi-Di Sun: Chinese Academy of Sciences
Jia Fan: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Intratumoral 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.

Date: 2024
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DOI: 10.1038/s41467-024-44795-1

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