Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing

Dieke J. van Rees, Maximilian Brinkhaus, Bart Klein, Paul Verkuijlen, Anton T.J. Tool, Karin Schornagel, Louise W. Treffers, Michel van Houdt, Arnon P. Kater, Gestur Vidarsson, Andrew R. Gennery, Taco W. Kuijpers, Robin van Bruggen, Hanke L. Matlung, Timo K. van den Berg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPa checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPa interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies.

Original languageEnglish
Pages (from-to)2156–2166
Number of pages11
JournalBlood advances
Volume6
Issue number7
DOIs
Publication statusPublished - 12 Apr 2022

Bibliographical note

Funding Information:
This research was funded by a grant from the Dutch Cancer Society (11537).

Funding Information:
Conflict-of-interest disclosure: T.K.v.d.B. is the inventor of patent EP2282772, owned by Stichting Sanquin Bloedvoorzi-ening, entitled “Compositions and Methods to Enhance the Immune System,” which describes targeting CD47-SIRPa interactions during antibody therapy in cancer. A.P.K. received research funding from Celgene, AbbVie, Roche, Janssen, and Astra-Zeneca and speaker’s fees from AbbVie and is active on the advisory boards of Janssen, Astra-Zeneca, and AbbVie. M.B. is funded by argenx. The remaining authors declare no competing financial interests.

Publisher Copyright:
© 2022 by The American Society of Hematology.

Keywords

  • Antibody
  • Cd20
  • Complement
  • Dependent cellular cytotoxicity
  • Expression
  • Fc-gamma-r
  • Phosphatase inhibitor
  • Rituximab
  • Sirp-alpha
  • Therapeutic activity

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