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

作者：Tingxuan Gu, Xueli Tian, Yuanyuan Wang, Wenqian Yang, Wenwen Li, Mengqiu Song, Ran Zhao, Mengqiao Wang, Quanli Gao, Tiepeng Li, Chengjuan Zhang, Joydeb Kumar Kundu, Kangdong Liu, Zigang Dong, Mee‐Hyun Lee · 发表于：Frontiers in Immunology · 年份：2023 · DOI：10.3389/fimmu.2023.1145028 · 被引用次数：9 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

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.