Oncotarget

Research Papers: Immunology:

High-affinity human PD-L1 variants attenuate the suppression of T cell activation

Zhaoduan Liang _, Ye Tian, Wenxuan Cai, Zhiming Weng, Yanyan Li, Huanling Zhang, Yifeng Bao and Yi Li

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Oncotarget. 2017; 8:88360-88375. https://doi.org/10.18632/oncotarget.21729

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Abstract

Zhaoduan Liang1, Ye Tian1, Wenxuan Cai1, Zhiming Weng3, Yanyan Li1, Huanling Zhang1,2, Yifeng Bao1 and Yi Li1,3

1 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

2 School of Life Sciences, University of Science and Technology of China, Hefei, China

3 XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd., Guangzhou, China

Correspondence to:

Yi Li, email:

Keywords: high affinity, programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1), soluble PD-L1, T cell, Immunology and Microbiology Section, Immune response, Immunity

Received: August 15, 2017 Accepted: September 03, 2017 Published: October 10, 2017

Abstract

The activated T cells can be suppressed by programed death-1 (PD-1) axis through low affinity interaction between PD-1 and PD-ligand 1 (PD-L1) in solution or on antigen presenting cells. In clinic, the concentration of soluble PD-L1 in peripheral blood negatively correlates with cancer prognosis. However, there is little information about the relation between the affinity of PD-1/PD-L1 interaction and the suppressive capacity of PD-1 axis. In this study, we analyzed inhibitory roles of high affinity soluble human PD-L1 (hPD-L1) variants, which were generated with directed molecular evolution. Resultant two clones L3C7-hPD-L1 and L3B3-hPD-L1 showed over 20 folds greater affinity than that of native hPD-L1. We found that L3B3-hPD-L1 and L3C7-hPD-L1 could compete with an anti-PD-1 antibody (EH12.1) for binding to hPD-1. More importantly, although native soluble hPD-L1 can induce suppressive effects on activated T cells, we found L3B3-hPD-L1 and L3C7-hPD-L1 attenuated the strength of PD-1 axis for suppressing the proliferation and interferon γ (IFN-γ) secretion of PBMC. In conclusion, our data provide direct evidence in which immune checkpoint receptor-ligand interactive strength can alter the the suppressive function, in particular, the suppressive capacity of PD-1 axis could be decreased with enhanced affinity of soluble PD-L1 and PD-1 interaction. Our study might provide a new direction for manipulating immune checkpoints.


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