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

Zhenzhen Fan, Yahui Tian, Zhipeng Chen, Lu Liu, Qian Zhou, Jingjing He, James Coleman, Changjiang Dong, Nan Li, Junqi Huang, Chenqi Xu, Zhimin Zhang, Song Gao, Penghui Zhou, Ke Ding, Liang Chen

Research output: Contribution to journalArticle

5 Citations (Scopus)
14 Downloads (Pure)

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.
Original languageEnglish
Article numbere11571
Number of pages17
JournalEMBO Molecular Medicine
Volume12
Issue number6
Early online date11 May 2020
DOIs
Publication statusPublished - 8 Jun 2020

Keywords

  • PD-1
  • immunotherapy
  • methylene blue
  • small molecular inhibitor
  • transgenic mouse model

Cite this