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

• Published in: Frontiers in immunology Vol. 14; p. 1145028
• Main Authors: Gu, Tingxuan, Tian, Xueli, Wang, Yuanyuan, Yang, Wenqian, Li, Wenwen, Song, Mengqiu, Zhao, Ran, Wang, Mengqiao, Gao, Quanli, Li, Tiepeng, Zhang, Chengjuan, Kundu, Joydeb Kumar, Liu, Kangdong, Dong, Zigang, Lee, Mee-Hyun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 02.05.2023
• Subjects: Animals; anti-cancer; B7-H1 Antigen; cancer; immune checkpoint; Immunology; Immunotherapy; Mice; Neoplasms - therapy; PD-1/PD-L1 signaling; pentamidine; Pentamidine - pharmacology; Programmed Cell Death 1 Receptor; PD-1/PD-L1 signaling; drug repurposing; pentamidine; immune checkpoint; immunotherapy; cancer; anti-cancer
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1145028

Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses 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 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. 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.