Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Matlung, Hanke L.; Babes, Liane; Zhao, Xi; Houdt, Michel van; Treffers, Louise W.; Rees, Dieke J van; Franke, Katka; Schornagel, Karin; Verkuijlen, Paul; Janssen, Hans; Halonen, Pasi; Lieftink, Cor; Beijersbergen, Roderick L.; Leusen, Jeanette H.W.; Boelens, Jaap Jan; Kühnle, Ingrid; Bosch, Jutte van der Werff ten; Seeger, Karl; Rutella, Sergio; Pagliara, Daria; Matozaki, Takashi; Suzuki, Eiji; Oordt, C. Willemien Menke-van der Houven van; Bruggen, Robin van; Roos, Dirk; Lier, René A. W. van; Kuijpers, Taco W.; Kubes, Paul; Berg, Timo K. van den

doi:10.1016/j.celrep.2018.05.082

Cited by 292 publications

(411 citation statements)

References 69 publications

(95 reference statements)

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“…4E). Next, we were interested to analyze the mechanism of IgG2-mediated tumor cell killing by PMN, which was recently reported to be induced by trogocytosis (29). Incubation of PMN with DiO-membrane labeled A431 cells resulted in the uptake of tumor cell membranes by PMN in the presence of EGFR antibodies ( Fig.…”

Section: Egfr-directed Igg2 Antibodies Activate M1-like Macrophages Fmentioning

confidence: 99%

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Immune Effector Functions of Human IgG2 Antibodies against EGFR

Rösner

Kahle

Montenegro

et al. 2019

Molecular Cancer Therapeutics

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Three FDA-approved epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab, necitumumab) are clinically available to treat patients with different types of cancers. Interestingly, panitumumab is of human IgG2 isotype, which is often considered to have limited immune effector functions. Unexpectedly, our studies unraveled that human IgG2 antibodies against EGFR mediated effective CDC when combined with another noncrossblocking EGFR antibody. This second antibody could be of human IgG1 or IgG2 isotype. Furthermore, EGFR antibodies of human IgG2 isotype were highly potent in recruiting myeloid effector cells such as M1 macrophages and PMN for tumor cell killing by ADCC. Tumor cell killing by PMN was more effective with IgG2 than with IgG1 antibodies if tumor cells expressed lower levels of EGFR. Additionally, lower expression levels of the "don't eat me" molecule CD47 on tumor cells enabled ADCC also by M2 macrophages, and improved PMN and macrophage-mediated ADCC. A TCGA enquiry revealed broadly varying CD47 expression levels across different solid tumor types. Together, these results demonstrate that human IgG2 antibodies against EGFR can promote significant Fc-mediated effector functions, which may contribute to their clinical efficacy. The future challenge will be to identify clinical situations in which myeloid effector cells can optimally contribute to antibody efficacy.

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Section: Egfr-directed Igg2 Antibodies Activate M1-like Macrophages Fmentioning

confidence: 99%

“…The transfer of membrane from tumor cells to neutrophils was measured by flow cytometry as described (29). Briefly, lamin-B-TRQ-transfected A431 cells were labeled at 37 C with the lipophilic membrane dye DiO (5 mmol/L, Invitrogen).…”

Section: Trogocytosis Assaymentioning

confidence: 99%

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Rösner

Kahle

Montenegro

et al. 2019

Molecular Cancer Therapeutics

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“…The previous paradigm was that microbes engage trogocytosis for cell-killing, but trogocytosis in multicellular organisms was believed to be a benign form of cell-cell interaction. However, recent reports have now shown that neutrophils can use trogocytosis to kill parasites [29], and that neutrophils and macrophages can use trogocytosis to kill cancer cells in a form of antibody-dependent cell-mediated cytotoxicity [30,31]. Trogocytosis is therefore likely to be a conserved, fundamental form of eukaryotic cell-cell interaction that can be cytotoxic or benign, depending on the context.…”

Section: Introductionmentioning

confidence: 99%

Trogocytosis by Entamoeba histolytica mediates acquisition and display of human cell membrane proteins and evasion of lysis by human serum

Miller

Suleiman

Ralston

2018

Preprint

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Entamoeba histolytica is the protozoan parasite responsible for amoebiasis. We previously showed that E. histolytica kills human cells through a mechanism that we termed trogocytosis (trogo-: nibble), due to its resemblance to trogocytosis in other organisms. In parasites, trogocytosis is used to kill host cells. In multicellular organisms, trogocytosis is used for cell-cell interactions in the immune system, in the central nervous system, and during development. Thus, nibbling is an emerging theme in cell-cell interactions both within and between species, and it is relevant to host-pathogen interactions in many different contexts. When trogocytosis occurs between mammalian immune cells, cell membrane proteins from the nibbled cell can be acquired and displayed by the recipient cell. In this study, we tested the hypothesis that through trogocytosis of human cells, amoebae acquire and display human cell membrane proteins. Here we demonstrate for the first time that through trogocytosis, E. histolytica acquires and displays human cell membrane proteins and that this leads to protection from lysis by human serum. Protection from human serum only occurs after amoebae have undergone trogocytosis of live cells, but not phagocytosis of dead cells. Likewise, mutant amoebae that exhibit a phagocytosis defect, but are unaltered in their capacity to perform trogocytosis, are nevertheless protected from human serum. Our studies are the first to demonstrate that amoebae can display human cell membrane proteins and suggest that acquisition and display of membrane proteins is a general feature of trogocytosis that is not restricted to trogocytosis between mammalian immune cells. These studies have major implications for interactions between E. histolytica and the immune system and also reveal a novel strategy for immune evasion by a pathogen. Since other microbial eukaryotes use trogocytosis for cell killing, our findings may apply to the pathogenesis of other infections.

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“…It was recently shown that neutrophils can detach and engulf fragments of Trichomonas vaginalis, using a process called trogocytosis [22][23][24][25] . Neutrophils can also kill cancer cells using trogocytosis 26 . The nibbling process of trogocytosis shows that neutrophils have the ability to remove small pieces from a large target before engulfing those pieces 26 .…”

Section: Introductionmentioning

confidence: 99%

“…Neutrophils can also kill cancer cells using trogocytosis 26 . The nibbling process of trogocytosis shows that neutrophils have the ability to remove small pieces from a large target before engulfing those pieces 26 . Phagocytosing Dictyostelium and Entamoeba can also break off and ingest small pieces of a target 27,28 .…”

Section: Introductionmentioning

confidence: 99%

Assaying how the success of phagocytosis depends on the mechanics of a large viscoelastic target

Davis-Fields¹,

Bakhtiari²,

Kovach³

et al. 2019

Preprint

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The state of the art does not provide a method for determining how the success of phagocytosis depends on the mechanics of a target that is much larger than the phagocytosing cell. We have developed such a method. We vary the elastic moduli of millimeter-sized abiotic gels that contain fluorescent beads to act as tracers for phagocytosis. We isolate human neutrophils, expose them to gels for one hour, and then measure what percentage of neutrophils contain beadsthis is our metric for successful phagocytosis. Both increased polymer concentration in agarose gels and increased crosslinking density in alginate gels are associated with decreased success of phagocytosis. When we plot the percentage of neutrophils containing beads as a function of the gel elastic modulus, we find that data from both alginate and agarose gels collapse onto the same curve. This demonstrates the utility of our method as a way of measuring how the viscoelastic mechanics of a large target impact the success of phagocytosis. Statement of Significance2 Bacterial biofilms are viscoelastic materials made of bacteria embedded in a matrix of extracellular polymers and proteins. Biofilm infections resist clearance by the immune system and have been shown to consist of multiple discrete aggregates, each approximately 100 m in diameter, that are densely surrounded, but not entered, by neutrophils that are approximately 10 m in diameter. Neutrophils are phagocytic immune cells that readily engulf bacterial cells that are not embedded within a biofilm community. For any phagocytic cell and any much-larger target, whether pieces of the target can be detached for subsequent engulfment must depend on both the force exerted by the cell and on the mechanics of the target. Our measurements also show that the success of phagocytosis depends strongly on elastic modulus for the range of elastic moduli that we previously measured for biofilms re-grown from clinical isolates (~0.05 -10 kPa).

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Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Cited by 292 publications

References 69 publications

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Trogocytosis by Entamoeba histolytica mediates acquisition and display of human cell membrane proteins and evasion of lysis by human serum

Assaying how the success of phagocytosis depends on the mechanics of a large viscoelastic target

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