RT Journal Article
SR Electronic
T1 Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47–SIRPα Checkpoint Disruption
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
DO 10.1158/2326-6066.CIR-20-0491
A1 Bouti, Panagiota
A1 Zhao, Xi Wen
A1 Verkuijlen, Paul J.J.H.
A1 Tool, Anton T.J.
A1 van Houdt, Michel
A1 Köker, Nezihe
A1 Köker, Mustafa Yavuz
A1 Keskin, Ozlem
A1 Akbayram, Sinan
A1 van Bruggen, Robin
A1 Kuijpers, Taco W.
A1 Matlung, Hanke L.
A1 van den Berg, Timo K.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/early/2021/01/14/2326-6066.CIR-20-0491.abstract
AB 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.