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

• Published in: Nature communications 2024-01, Vol.15 (1), p.621-621, Article 621
• Main Authors: Lu, Jia-Cheng, 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-Ming, Zhou, Jian, Sun, Yi-Di, Fan, Jia
• Format: Article
• Language: English
• Subjects: 13/31; 38/47; 692/4020/4021; 692/4028/67/327; 692/4028/67/580; 82/1; Antibodies; Apoptosis Regulatory Proteins; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - pathology; Bile Ducts, Intrahepatic; Cancer therapies; CD8 antigen; CD8-Positive T-Lymphocytes; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; CTLA-4 protein; Gemcitabine; Gene sequencing; Humanities and Social Sciences; Humans; Immune status; Immunotherapy; Lymphocytes; Lymphocytes T; multidisciplinary; Oxaliplatin; Oxaliplatin - therapeutic use; PD-1 protein; Phenylurea Compounds; Quinolines; Receptors, Scavenger; Science; Science (multidisciplinary); T cell receptors; Therapy; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44795-1

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. The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.