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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Molecular and Cellular Oncology
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1488668
This article is part of the Research Topic New Insights on Sialic Acid and Sialylated Glycans in the Tumorigenic Process View all 4 articles

Sialylation inhibition improves macrophage mediated tumor cell phagocytosis of breast cancer cells triggered by therapeutic antibodies of different isotypes

Provisionally accepted
Marta Lustig Marta Lustig 1*Christoph Hahn Christoph Hahn 1Marie Leangen Herigstad Marie Leangen Herigstad 2,3,4Jan T. Andersen Jan T. Andersen 2,3,4Jeanette Leusen Jeanette Leusen 5Renate Burger Renate Burger 1Thomas Valerius Thomas Valerius 1
  • 1 Division of Antibody-Based Immunotherapy, Department of Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Schleswig-Holstein, Germany
  • 2 Institute for Clinical Medicine, Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
  • 3 Institute for Clinical Medicine, Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway
  • 4 Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway
  • 5 Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, Netherlands

The final, formatted version of the article will be published soon.

    Tumor cell phagocytosis by macrophages is considered a relevant mechanism of action for many therapeutic IgG antibodies. However, tumor cells employ several mechanisms to evade immune recognition, including hypersialylation. Here, we describe how reduction of sialic acid exposure on tumor cells promotes antibody-dependent tumor cell phagocytosis (ADCP) by macrophages. Incubation with the sialyltransferase inhibitor (STi) P-3Fax-Neu5Ac reduced sialylation on two breast cancer cell lines, rendering these cells more susceptible to macrophage mediated phagocytosis by EGFR or HER-2 antibodies. This was observed with not only IgG1 and IgG2 antibodies but also IgA2 variants. These results show that inhibiting sialic acid exposure triggers enhanced tumor cell phagocytosis by macrophages irrespective of the antibody isotype and the tumor target antigen. Investigating the underlying mechanisms of enhanced ADCP, we observed reduced binding of soluble sialic acid-binding immunoglobulinlike lectins (Siglec)-7 and Siglec-9 to tumor cells after sialylation inhibition. However, Fc silent blocking antibodies against Siglec-7 or Siglec-9, or their combination, only marginally improved ADCP. Our results further promote the concept of cancer hypersialylation as immune escape mechanism, which could serve as target to improve tumor immunotherapy with monoclonal antibodies.

    Keywords: Immune checkpoint, sialic acid, Siglecs, Myeloid Cells, therapeutic antibodies, IgG, IgA

    Received: 30 Aug 2024; Accepted: 06 Nov 2024.

    Copyright: © 2024 Lustig, Hahn, Leangen Herigstad, Andersen, Leusen, Burger and Valerius. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Marta Lustig, Division of Antibody-Based Immunotherapy, Department of Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Schleswig-Holstein, Germany

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