PT  - JOURNAL ARTICLE
AU  - Dieke J van Rees
AU  - Panagiota Bouti
AU  - Bart Klein
AU  - Paul J H Verkuijlen
AU  - Michel van Houdt
AU  - Karin Schornagel
AU  - Anton T J Tool
AU  - David Venet
AU  - Christos Sotiriou
AU  - Sarra El-Abed
AU  - Miguel Izquierdo
AU  - Sébastien Guillaume
AU  - Cristina Saura
AU  - Serena Di Cosimo
AU  - Jens Huober
AU  - Rebecca Roylance
AU  - Sung-Bae Kim
AU  - Taco W Kuijpers
AU  - Robin van Bruggen
AU  - Timo K van den Berg
AU  - Hanke L Matlung
TI  - Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex
AID  - 10.1136/jitc-2022-004820
DP  - 2022 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e004820
VI  - 10
IP  - 6
4099  - http://jitc.bmj.com/content/10/6/e004820.short
4100  - http://jitc.bmj.com/content/10/6/e004820.full
SO  - J Immunother Cancer2022 Jun 01; 10
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.