Repurposing pentamidine for cancer immunotherapy by targeting the PD1/PD-L1 immune checkpoint

Frontiers in Immunology

Immunology

Chengjuan Zhang¹  Quanli Gao¹  Tiepeng Li²  Wenwen Li³  Wenqian Yang⁴  Ran Zhao⁴  Xueli Tian⁴  Mengqiu Song⁴  Zigang Dong⁴  Yuanyuan Wang⁴  Tingxuan Gu⁴  Mengqiao Wang⁴  Kangdong Liu⁵  Mee-Hyun Lee⁶  Joydeb Kumar Kundu⁷ 

[1] Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China;Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China;Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China;Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China;China-US (Henan) Hormel Cancer Institute, Zhengzhou, China;Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China;China-US (Henan) Hormel Cancer Institute, Zhengzhou, China;Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China;Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China;China-US (Henan) Hormel Cancer Institute, Zhengzhou, China;Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China;College of Korean Medicine, Dongshin University, Naju, Republic of Korea;Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada;

关键词: PD-1/PD-L1 signaling;    pentamidine;    immune checkpoint;    immunotherapy;    cancer;    anti-cancer;    drug repurposing;   

DOI  :  10.3389/fimmu.2023.1145028

 received in 2023-01-15, accepted in 2023-04-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses via the blockade of immune checkpoint markers, such as program cell death-1 (PD-1) or its cognate ligand PD-L1, has been the basis for developing clinically effective anticancer therapies. We identified pentamidine, an FDA-approved antimicrobial agent, as a small-molecule antagonist of PD-L1. Pentamidine enhanced T-cell-mediated cytotoxicity against various cancer cells in vitro by increasing the secretion of IFN-γ, TNF-α, perforin, and granzyme B in the culture medium. Pentamidine promoted T-cell activation by blocking the PD-1/PD-L1 interaction. In vivo administration of pentamidine attenuated the tumor growth and prolonged the survival of tumor-bearing mice in PD-L1 humanized murine tumor cell allograft models. Histological analysis of tumor tissues showed an increased number of tumor-infiltrating lymphocytes in tissues derived from pentamidine-treated mice. In summary, our study suggests that pentamidine holds the potential to be repurposed as a novel PD-L1 antagonist that may overcome the limitations of monoclonal antibody therapy and can emerge as a small molecule cancer immunotherapy.

【 授权许可】

Unknown   
Copyright © 2023 Gu, Tian, Wang, Yang, Li, Song, Zhao, Wang, Gao, Li, Zhang, Kundu, Liu, Dong and Lee