RT Journal Article
SR Electronic
T1 Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e004820
DO 10.1136/jitc-2022-004820
VO 10
IS 6
A1 Dieke J van Rees
A1 Panagiota Bouti
A1 Bart Klein
A1 Paul J H Verkuijlen
A1 Michel van Houdt
A1 Karin Schornagel
A1 Anton T J Tool
A1 David Venet
A1 Christos Sotiriou
A1 Sarra El-Abed
A1 Miguel Izquierdo
A1 Sébastien Guillaume
A1 Cristina Saura
A1 Serena Di Cosimo
A1 Jens Huober
A1 Rebecca Roylance
A1 Sung-Bae Kim
A1 Taco W Kuijpers
A1 Robin van Bruggen
A1 Timo K van den Berg
A1 Hanke L Matlung
YR 2022
UL http://jitc.bmj.com/content/10/6/e004820.abstract
AB 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 (Ca2+)-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 Ca2+-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.Data are available upon reasonable request.