Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex.

Autor:	van Rees DJ; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., Bouti P; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands P.Bouti@sanquin.nl., Klein B; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., Verkuijlen PJH; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., van Houdt M; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., Schornagel K; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., Tool ATJ; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., Venet D; Breast Cancer Translational Research Laboratory JC Heuson, Institut Jules Bordet, Bruxelles, Belgium., Sotiriou C; Breast Cancer Translational Research Laboratory JC Heuson, Institut Jules Bordet, Bruxelles, Belgium., El-Abed S; Breast International Group, Brussels, Belgium., Izquierdo M; Novartis Pharma AG, Basel, Switzerland., Guillaume S; Department of Psychiatric Emergency & Acute Care, Lapeyronie Hospital, Montpellier, France., Saura C; SOLTI Innovative Breast Cancer Research, Vall d'Hebron Hospital Universitari, Barcelona, Spain., Di Cosimo S; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Huober J; Breast Center, University of Ulm, Ulm, Germany., Roylance R; Department of Oncology, University College London Hospitals NHS Foundation Trust and NIHR University College London Hospitals Biomedical Research Centre, London, UK., Kim SB; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Kuijpers TW; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands.; Department of Pediatric Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., van Bruggen R; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands., van den Berg TK; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands.; Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Matlung HL; Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jun; Vol. 10 (6).
DOI:	10.1136/jitc-2022-004820
Abstrakt:	Background: Neutrophils kill antibody-opsonized tumor cells using trogocytosis, a unique mechanism of destruction of the target plasma. This previously unknown cytotoxic process of neutrophils is dependent on antibody opsonization, Fcγ receptors and CD11b/CD18 integrins. Here, we demonstrate that tumor cells can escape neutrophil-mediated cytotoxicity by calcium (Ca 2+ )-dependent and exocyst complex-dependent plasma membrane repair. Methods: We knocked down EXOC7 or EXOC4, two exocyst components, to evaluate their involvement in tumor cell membrane repair after neutrophil-induced trogocytosis. We used live cell microscopy and flow cytometry for visualization of the host and tumor cell interaction and tumor cell membrane repair. Last, we reported the mRNA levels of exocyst in breast cancer tumors in correlation to the response in trastuzumab-treated patients. Results: We found that tumor cells can evade neutrophil antibody-dependent cellular cytotoxicity (ADCC) by Ca 2+ -dependent cell membrane repair, a process induced upon neutrophil trogocytosis. Absence of exocyst components EXOC7 or EXOC4 rendered tumor cells vulnerable to neutrophil-mediated ADCC (but not natural killer cell-mediated killing), while neutrophil trogocytosis remained unaltered. Finally, mRNA levels of exocyst components in trastuzumab-treated patients were inversely correlated to complete response to therapy. Conclusions: Our results support that neutrophil attack towards antibody-opsonized cancer cells by trogocytosis induces an active repair process by the exocyst complex in vitro. Our findings provide insight to the possible contribution of neutrophils in current antibody therapies and the tolerance mechanism of tumor cells and support further studies for potential use of the exocyst components as clinical biomarkers. Competing Interests: Competing interests: TKvdB is the inventor of patent EP2282772, owned by Stichting Sanquin Bloedvoorziening, entitled ‘Compositions and Methods to Enhance the Immune System’, which describes targeting CD47–SIRPα interactions during antibody therapy in cancer. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu