2. Academic Validation
  3. Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer

Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer

  • Eur J Med Chem. 2024 Feb 7:268:116182. doi: 10.1016/j.ejmech.2024.116182.
Jian-Gang Sun 1,  Ya Gao 2,  Yong-Shun Gao 3,  Xing-Jie Dai 4,  Peng Chen 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China.
  • 3 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: gaoys@zzu.edu.cn.
  • 4 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China. Electronic address: dxj@zzu.edu.cn.
  • 5 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: chenpengde220@163.com.
PMID: 38367489 DOI: 10.1016/j.ejmech.2024.116182
Abstract

Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric Cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric Cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC50 = 0.108 μM. By applying EP16 to gastric Cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric Cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric Cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation.

Keywords

CD63; Exosomes; Gastric cancer; PD-1; PD-L1.

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