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- Title
Repurposing pentamidine for cancer immunotherapy by targeting the PD1/PD-L1 immune checkpoint.
- Authors
Tingxuan Gu; Xueli Tian; Yuanyuan Wang; Wenqian Yang; Wenwen Li; Mengqiu Song; Ran Zhao; Mengqiao Wang; Quanli Gao; Tiepeng Li; Chengjuan Zhang; Kundu, Joydeb Kumar; Kangdong Liu; Zigang Dong; Mee-Hyun Lee
- Abstract
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-g, TNF-a, 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 tuPD-1/PD-L1 signaling, pentamidine, immune checkpoint, immunotherapy, cancer, anticancer, drug repurposingpotential 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.
- Subjects
IMMUNE checkpoint proteins; UNITED States. Food &; Drug Administration; BIOMARKERS; SMALL molecules; PROGRAMMED cell death 1 receptors; PROGRAMMED death-ligand 1
- Publication
Frontiers in Immunology, 2023, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2023.1145028