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 language | English |
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Pages (from-to) | 2156–2166 |
Number of pages | 11 |
Journal | Blood advances |
Volume | 6 |
Issue number | 7 |
DOIs | |
Publication status | Published - 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