Kindlin3-dependent CD11b/CD18-integrin activation is required for potentiation of neutrophil cytotoxicity by CD47-SIRPa checkpoint disruption
| Autor: | Robin van Bruggen, Anton T.J. Tool, Xi Wen Zhao, Taco W. Kuijpers, Nezihe Köker, Michel van Houdt, Mustafa Yavuz Köker, Paul Verkuijlen, Timo K. van den Berg, Panagiota Bouti, Hanke L. Matlung, Sinan Akbayram, Ozlem Keskin |
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| Přispěvatelé: | Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AR&D - Amsterdam Reproduction & Development, AII - Cancer immunology, CCA - Cancer biology and immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Integrins Cancer Research Trogocytosis Neutrophils Immunology CD47 Antigen CD18 Gene mutation 03 medical and health sciences Congenital Disorders of Glycosylation 0302 clinical medicine medicine Humans Leukocyte adhesion deficiency Antibody-dependent cell-mediated cytotoxicity CD11b Antigen biology Chemistry CD47 Antibody-Dependent Cell Cytotoxicity Membrane Proteins medicine.disease Antigens Differentiation Immune checkpoint Neoplasm Proteins Cell biology 030104 developmental biology Integrin alpha M CD18 Antigens 030220 oncology & carcinogenesis Mutation biology.protein |
| Zdroj: | Cancer immunology research, 9(2), 147-155. American Association for Cancer Research Inc. |
| ISSN: | 2326-6066 |
| Popis: | 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 carryingFERMT3gene 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 |
| Databáze: | OpenAIRE |
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