TY - JOUR
T1 - Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing
AU - van Rees, Dieke J.
AU - Brinkhaus, Maximilian
AU - Klein, Bart
AU - Verkuijlen, Paul
AU - Tool, Anton T. J.
AU - Schornagel, Karin
AU - Treffers, Louise W.
AU - van Houdt, Michel
AU - Kater, Arnon P.
AU - Vidarsson, Gestur
AU - Gennery, Andrew R.
AU - Kuijpers, Taco W.
AU - van Bruggen, Robin
AU - Matlung, Hanke L.
AU - van den Berg, Timo K.
N1 - 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.
PY - 2022/4/12
Y1 - 2022/4/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85128325685&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34942000
UR - http://www.scopus.com/inward/record.url?scp=85128325685&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/bloodadvances.2021005367
DO - https://doi.org/10.1182/bloodadvances.2021005367
M3 - Article
C2 - 34942000
SN - 2473-9529
VL - 6
SP - 2156
EP - 2166
JO - Blood
JF - Blood
IS - 7
ER -