Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Fan, Zhenzhen, Tian, Yahui, Chen, Zhipeng, Liu, Lu, Zhou, Qian, He, Jingjing, Coleman, James, Dong, Changjiang, Li, Nan, Huang, Junqi, Xu, Chenqi, Zhang, Zhimin, Gao, Song, Zhou, Penghui, Ding, Ke and Chen, Liang (2020) Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors. EMBO Molecular Medicine, 12 (6). ISSN 1757-4676

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Abstract

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis.

Item Type: Article
Uncontrolled Keywords: pd-1,immunotherapy,methylene blue,small molecular inhibitor,transgenic mouse model,molecular medicine ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 21 May 2020 00:24
Last Modified: 18 Oct 2020 00:00
URI: https://ueaeprints.uea.ac.uk/id/eprint/75277
DOI: 10.15252/emmm.201911571

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