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Cancer Immunology Research
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Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47–SIRPα Checkpoint Disruption

Panagiota Bouti, Xi Wen Zhao, Paul J.J.H. Verkuijlen, Anton T.J. Tool, Michel van Houdt, Nezihe Köker, Mustafa Yavuz Köker, Ozlem Keskin, Sinan Akbayram, Robin van Bruggen, Taco W. Kuijpers, Hanke L. Matlung and Timo K. van den Berg
Panagiota Bouti
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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  • For correspondence: p.bouti@sanquin.nl t.k.vandenberg@sanquin.nl
Xi Wen Zhao
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Paul J.J.H. Verkuijlen
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Anton T.J. Tool
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Michel van Houdt
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Nezihe Köker
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
2Department of Immunology, Erciyes University Medical Faculty, Kayseri, Turkey.
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  • ORCID record for Nezihe Köker
Mustafa Yavuz Köker
2Department of Immunology, Erciyes University Medical Faculty, Kayseri, Turkey.
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Ozlem Keskin
3Pediatric Allergy and Immunology, Gaziantep University, Gaziantep, Turkey.
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Sinan Akbayram
4Department of Pediatric Hematology-Oncology, Gaziantep University Medical Faculty, Gaziantep, Turkey.
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Robin van Bruggen
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Taco W. Kuijpers
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
5Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands.
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Hanke L. Matlung
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Timo K. van den Berg
1Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
6Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Vrije University, Amsterdam, the Netherlands.
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  • For correspondence: p.bouti@sanquin.nl t.k.vandenberg@sanquin.nl
DOI: 10.1158/2326-6066.CIR-20-0491 Published February 2021
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Abstract

The CD47–signal regulatory protein-alpha (SIRPα) immune checkpoint constitutes a therapeutic target in cancer, and initial clinical studies using inhibitors of CD47–SIRPα interactions in combination with tumor-targeting antibodies show promising results. Blockade of CD47–SIRPα interaction can promote neutrophil antibody-dependent cellular cytotoxicity (ADCC) toward antibody-opsonized targets. Neutrophils induce killing of antibody-opsonized tumor cells by a process identified as trogoptosis, a necrotic/lytic type of cancer cell death that involves trogocytosis, the antibody-mediated endocytic acquisition of cancer membrane fragments by neutrophils. Both trogocytosis and killing strictly depend on CD11b/CD18-(Mac-1)–mediated neutrophil–cancer cell conjugate formation, but the mechanism by which CD47–SIRPα checkpoint disruption promotes cytotoxicity has remained elusive. Here, by using neutrophils from patients with leukocyte adhesion deficiency type III carrying FERMT3 gene mutations, hence lacking the integrin-associated protein kindlin3, we demonstrated that CD47–SIRPα signaling controlled the inside-out activation of the neutrophil CD11b/CD18-integrin and cytotoxic synapse formation in a kindlin3-dependent fashion. Our findings also revealed a role for kindlin3 in trogocytosis and an absolute requirement in the killing process, which involved direct interactions between kindlin3 and CD18 integrin. Collectively, these results identified a dual role for kindlin3 in neutrophil ADCC and provide mechanistic insights into the way neutrophil cytotoxicity is governed by CD47–SIRPα interactions.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:147–55

  • Received June 10, 2020.
  • Revision received October 7, 2020.
  • Accepted December 9, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (2)
February 2021
Volume 9, Issue 2
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Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47–SIRPα Checkpoint Disruption
Panagiota Bouti, Xi Wen Zhao, Paul J.J.H. Verkuijlen, Anton T.J. Tool, Michel van Houdt, Nezihe Köker, Mustafa Yavuz Köker, Ozlem Keskin, Sinan Akbayram, Robin van Bruggen, Taco W. Kuijpers, Hanke L. Matlung and Timo K. van den Berg
Cancer Immunol Res February 1 2021 (9) (2) 147-155; DOI: 10.1158/2326-6066.CIR-20-0491

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Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47–SIRPα Checkpoint Disruption
Panagiota Bouti, Xi Wen Zhao, Paul J.J.H. Verkuijlen, Anton T.J. Tool, Michel van Houdt, Nezihe Köker, Mustafa Yavuz Köker, Ozlem Keskin, Sinan Akbayram, Robin van Bruggen, Taco W. Kuijpers, Hanke L. Matlung and Timo K. van den Berg
Cancer Immunol Res February 1 2021 (9) (2) 147-155; DOI: 10.1158/2326-6066.CIR-20-0491
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