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

Vittoria Lopez; H J Maximilian Schuh; Salahuddin Mirza; Victoria J Vaaßen; Michael S Schmidt; Katharina Sylvester; Riham M Idris; Christian Renn; Laura Schäkel; Julie Pelletier; Jean Sévigny; Annamaria Naggi; Björn Scheffler; Sang-Yong Lee; Gerd Bendas; Christa E Müller

doi:10.3389/fimmu.2023.1173634

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

Front Immunol. 2023 Aug 29:14:1173634. doi: 10.3389/fimmu.2023.1173634. eCollection 2023.

Authors

Vittoria Lopez^{1

2}, H J Maximilian Schuh³, Salahuddin Mirza^{1

2}, Victoria J Vaaßen^{1

2}, Michael S Schmidt³, Katharina Sylvester^{1

2}, Riham M Idris^{1

2}, Christian Renn^{1

2}, Laura Schäkel^{1

2}, Julie Pelletier⁴, Jean Sévigny^{4

5}, Annamaria Naggi⁶, Björn Scheffler⁷, Sang-Yong Lee^{1

2}, Gerd Bendas³, Christa E Müller^{1

2}

Affiliations

¹ Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany.
² PharmaCenter Bonn, University of Bonn, Bonn, Germany.
³ Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, Bonn, Germany.
⁴ Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada.
⁵ Départment de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Quebec, QC, Canada.
⁶ Institute for Chemical and Biochemical Research "G. Ronzoni", Milan, Italy.
⁷ DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner site, University Hospital Essen and German Cancer Research Center, Heidelberg, Germany.

Abstract

Introduction: Heparins, 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 results: In 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.

Discussion: NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.

Keywords: NPP1; U87 glioblastoma cells; adenosine; ectonucleotidase inhibitors; heparin; immuno-oncology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anticoagulants
Glioma*
Heparin* / pharmacology
Heparin, Low-Molecular-Weight / pharmacology
Heparin, Low-Molecular-Weight / therapeutic use
Humans
Immunotherapy

Substances

Heparin
Anticoagulants
Heparin, Low-Molecular-Weight

Grants and funding

This study was funded by the Federal Ministry of Education and Research (BMBF, BIGS DrugS project) and by the Deutsche Forschungsgemeinschaft (DFG, SFB1328, Project-ID: 335447717). JS received support from the Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN-2016-05867).