Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phospho-diesterase-1 (NPP1) – a promising target for the immunotherapy of cancer

Frontiers in Immunology

Immunology

Julie Pelletier¹  Jean Sévigny²  Björn Scheffler³  Annamaria Naggi⁴  H. J. Maximilian Schuh⁵  Gerd Bendas⁵  Michael S. Schmidt⁵  Laura Schäkel⁶  Vittoria Lopez⁶  Sang-Yong Lee⁶  Victoria J. Vaaßen⁶  Christian Renn⁶  Salahuddin Mirza⁶  Christa E. Müller⁶  Katharina Sylvester⁶  Riham M. Idris⁶ 

[1] Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada;Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada;Départment de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, Quebec, QC, Canada;DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner site, University Hospital Essen and German Cancer Research Center, Heidelberg, Germany;Institute for Chemical and Biochemical Research “G. Ronzoni”, Milan, Italy;Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, Bonn, Germany;Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany;PharmaCenter Bonn, University of Bonn, Bonn, Germany;

关键词: adenosine;    ectonucleotidase inhibitors;    immuno-oncology;    NPP1;    U87 glioblastoma cells;    heparin;   

DOI  :  10.3389/fimmu.2023.1173634

 received in 2023-02-24, accepted in 2023-07-03,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionHeparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy.Methods and resultsIn the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds’ antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells.DiscussionNPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.

【 授权许可】

Unknown   
Copyright © 2023 Lopez, Schuh, Mirza, Vaaßen, Schmidt, Sylvester, Idris, Renn, Schäkel, Pelletier, Sévigny, Naggi, Scheffler, Lee, Bendas and Müller