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

Cancer Immunol Res. 2021 Feb;9(2):147-155. doi: 10.1158/2326-6066.CIR-20-0491. Epub 2020 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antigens, Differentiation / immunology
  • CD11b Antigen / immunology*
  • CD18 Antigens / immunology*
  • CD47 Antigen / antagonists & inhibitors*
  • CD47 Antigen / immunology
  • Congenital Disorders of Glycosylation / genetics
  • Congenital Disorders of Glycosylation / immunology
  • Congenital Disorders of Glycosylation / pathology
  • Humans
  • Integrins / metabolism*
  • Membrane Proteins / genetics
  • Mutation
  • Neoplasm Proteins / genetics
  • Neutrophils / immunology*


  • Antigens, Differentiation
  • CD11b Antigen
  • CD18 Antigens
  • CD47 Antigen
  • CD47 protein, human
  • FERMT3 protein, human
  • ITGAM protein, human
  • Integrins
  • Membrane Proteins
  • Neoplasm Proteins

Supplementary concepts

  • Congenital disorder of glycosylation, type 2C