TY - JOUR
T1 - Kindlin3-dependent CD11b/CD18-integrin activation is required for potentiation of neutrophil cytotoxicity by CD47-SIRPa checkpoint disruption
AU - Bouti, Panagiota
AU - Zhao, Xi Wen
AU - Verkuijlen, Paul J. J. H.
AU - Tool, Anton T. J.
AU - van Houdt, Michel
AU - Köker, Nezihe
AU - Köker, Mustafa Yavuz
AU - Keskin, Ozlem
AU - Akbayram, Sinan
AU - van Bruggen, Robin
AU - Kuijpers, Taco W.
AU - Matlung, Hanke L.
AU - van den Berg, Timo K.
N1 - Funding Information: This work was supported by the Dutch Cancer Society (grant numbers 10300 and 11537) and the Erciyes University (BAP-TYL-2020-10064). Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - The CD47-signal regulatory protein-alpha (SIRPa) immune checkpoint constitutes a therapeutic target in cancer, and initial clinical studies using inhibitors of CD47-SIRPa interactions in combination with tumor-targeting antibodies show promising results. Blockade of CD47-SIRPa 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-SIRPa 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-SIRPa 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-SIRPa interactions.
AB - The CD47-signal regulatory protein-alpha (SIRPa) immune checkpoint constitutes a therapeutic target in cancer, and initial clinical studies using inhibitors of CD47-SIRPa interactions in combination with tumor-targeting antibodies show promising results. Blockade of CD47-SIRPa 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-SIRPa 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-SIRPa 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-SIRPa interactions.
UR - http://www.scopus.com/inward/record.url?scp=85100441999&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/2326-6066.CIR-20-0491
DO - https://doi.org/10.1158/2326-6066.CIR-20-0491
M3 - Article
C2 - 33355195
SN - 2326-6066
VL - 9
SP - 147
EP - 155
JO - Cancer immunology research
JF - Cancer immunology research
IS - 2
ER -