PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression

Lin-Zhou Zhang, Jie-Gang Yang, Gai-Li Chen, Qi-Hui Xie, Qiu-Yun Fu, Hou-Fu Xia, Yi-Cun Li, Jue Huang, Ye Li, Min Wu, Hai-Ming Liu, Fu-Bing Wang, Ke-Zhen Yi, Huan-Gang Jiang, Fu-Xiang Zhou, Wei Wang, Zi-Li Yu, Wei Zhang, Ya-Hua Zhong, Zhuan Bian, Hong-Yu Yang, Bing Liu and Gang Chen ()
Additional contact information
Lin-Zhou Zhang: Wuhan University
Jie-Gang Yang: Wuhan University
Gai-Li Chen: Hubei Key Laboratory of Tumour Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University
Qi-Hui Xie: Wuhan University
Qiu-Yun Fu: Wuhan University
Hou-Fu Xia: Wuhan University
Yi-Cun Li: Peking University Shenzhen Hospital
Jue Huang: Wuhan University
Ye Li: Wuhan University
Min Wu: Wuhan University
Hai-Ming Liu: Wuhan University
Fu-Bing Wang: Zhongnan Hospital of Wuhan University
Ke-Zhen Yi: Zhongnan Hospital of Wuhan University
Huan-Gang Jiang: Hubei Key Laboratory of Tumour Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University
Fu-Xiang Zhou: Hubei Key Laboratory of Tumour Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University
Wei Wang: Renmin Hospital of Wuhan University
Zi-Li Yu: Wuhan University
Wei Zhang: Wuhan University
Ya-Hua Zhong: Hubei Key Laboratory of Tumour Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University
Zhuan Bian: Wuhan University
Hong-Yu Yang: Peking University Shenzhen Hospital
Bing Liu: Wuhan University
Gang Chen: Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Date: 2024
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DOI: 10.1038/s41467-024-48200-9

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