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

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 pa...

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Autores principales: 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, Chen, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278553/
https://www.ncbi.nlm.nih.gov/pubmed/32391629
http://dx.doi.org/10.15252/emmm.201911571
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author 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
Chen, Liang
author_facet 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
Chen, Liang
author_sort Fan, Zhenzhen
collection PubMed
description 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.
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spelling pubmed-72785532020-06-09 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 Chen, Liang EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2020-05-11 2020-06-08 /pmc/articles/PMC7278553/ /pubmed/32391629 http://dx.doi.org/10.15252/emmm.201911571 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
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
Chen, Liang
Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title_full Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title_fullStr Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title_full_unstemmed Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title_short Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors
title_sort blocking interaction between shp2 and pd‐1 denotes a novel opportunity for developing pd‐1 inhibitors
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278553/
https://www.ncbi.nlm.nih.gov/pubmed/32391629
http://dx.doi.org/10.15252/emmm.201911571
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