Therapeutic exploitation of neutrophils to fight cancer

Gruijs, Mandy; Sewnath, Celine Angeli Natascha; Egmond, Marjolein van

doi:10.1016/j.smim.2021.101581

Cited by 21 publications

(19 citation statements)

References 143 publications

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“…The role of neutrophils in host defense has been well‐recognized for a long time. However, more recently, attention has been drawn to the role of neutrophils in cancer 21–23 . High numbers of neutrophils have been observed in tumors, although it is still debated what functions these neutrophils may have in different TMEs 22,24,25 .…”

Section: The Controversial Role Of Neutrophils In Cancermentioning

confidence: 99%

“…However, more recently, attention has been drawn to the role of neutrophils in cancer. [21][22][23] High numbers of neutrophils have been observed in tumors, although it is still debated what functions these neutrophils may have in different TMEs. 22,24,25 Several studies have suggested that tumor-associated neutrophils (TANs) may promote tumor growth and metastasis while suppressing anti-tumor immune responses.…”

Section: The Controver S Ial Role Of Neutrophil S In C An Cermentioning

confidence: 99%

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Neutrophils as immune effector cells in antibody therapy in cancer

Behrens

Egmond

Berg³

2022

Immunological Reviews

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Over the last decades, new therapies have greatly improved the treatment of different cancer types. For example, immunotherapy is the collective of therapies that aims to recruit and stimulate the patient's own immune system to eradicate the tumor. 1 The tumor microenvironment (TME) comprises a great variety of cells, including endothelial cells, fibroblasts, and immune cells. Immune cells in the TME play a crucial role during cancer progression. Via immunosurveillance, immune cells are able to identify and eliminate malignant cells in the early stages. 2 However, certain mutations may cause adaptations that allow tumor cells to go undetected, for example, by downregulating MHC molecules. In addition, tumor cells may upregulate immunosuppressive molecules or secrete immunosuppressive cytokines to resist immune-mediated destruction. [3][4][5] Recruitment of immunosuppressive cells to the TME further polarizes the TME to an anti-inflammatory environment that prevents tumor killing and promotes disease progression. 6,7 Various types of agents to promote the immune system to eliminate tumor cells are in development or have become the standard of care in the treatment of cancer patients. This includes monoclonal antibodies (mAbs), adoptive (CAR) T cell transfer, or dendritic cell (DC) vaccination. Monoclonal antibodies include checkpoint inhibitors as well as tumor-associated antigen (TAA)-targeting antibodies directed against membrane components

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Section: The Controversial Role Of Neutrophils In Cancermentioning

confidence: 99%

Section: The Controver S Ial Role Of Neutrophil S In C An Cermentioning

confidence: 99%

Neutrophils as immune effector cells in antibody therapy in cancer

Behrens

Egmond

Berg³

2022

Immunological Reviews

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“…Given that neutrophils have the ability to kill antibody‐opsonized cancer cells through ADCC, 32 we also examined whether neutrophils might mediate the MY‐1‐mIgG2a‐dependent killing of CD11c + BMDCs from BRAF V600E CD11c mice in vitro. Incubation of CFSE‐labeled CD11c + BMDCs with neutrophils from the mutant mice for 4 h in the presence of MY‐1‐mIgG2a resulted in no significant promotion of target cell death compared with that apparent in the presence of control IgG (Figure S7 ), suggesting that MY‐1‐mIgG2a has a minimal effect on the killing activity of neutrophils for CD11c + BMDCs of the mutant mice.…”

Section: Resultsmentioning

confidence: 99%

Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from the anomalous accumulation of pathogenic CD1a + CD207 + dendritic cells (DCs). SIRPα is a transmembrane protein highly expressed in myeloid cells such as DCs and macrophages. Here we show that SIRPα is a potential therapeutic target for LCH. We found that SIRPα is expressed in CD1a + cells of human LCH lesions as well as in CD11c + DCs in the spleen, liver, and lung of a mouse model of LCH ( BRA FV600E CD11c mouse), in which an LCH‐associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAF V600E CD11c mice manifested markedly increased numbers of CD4 + T cells, regulatory T cells, and macrophages as well as of CD11c + MHCII + DCs in the spleen. Monotherapy with a mAb to SIRPα greatly reduced the percentage of CD11c + MHCII + DCs in peripheral blood, LCH‐like lesion size in the liver, and the number of CD11c + MHCII + DCs in the spleen of the mutant mice. Moreover, this mAb promoted macrophage‐mediated phagocytosis of CD11c + DCs from BRAF V600E CD11c mice, whereas it had no effects on the viability or CCL19‐dependent migration of such CD11c + DCs or on their expression of the chemokine genes Ccl5 , Ccl20 , Cxcl11 , and Cxcl12 . Our results thus suggest that anti‐SIRPα monotherapy is a promising approach to the treatment of LCH that is dependent in part on the promotion of the macrophage‐mediated killing of LCH cells.

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“…neutrophils, osteoclasts or CD103 + dendritic cells after crosslinking of their surface IgA Fc receptor (FcαRI, CD89) ( 6 – 9 ). In addition, it has been shown that anti-cancer (bispecific) antibodies targeting CD89 induce superior killing of tumor cells by neutrophils ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Antagonizing FcαR1 (CD89) as treatment in IgA-mediated chronic inflammation and autoimmunity

et al. 2023

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IntroductionImmunoglobulin A (IgA) is mostly considered as a non-inflammatory regulator at mucosal areas. However, previous work of our group showed that IgA can also be involved in disease pathology, because it provides a potent stimulus to activate neutrophils after crosslinking of surface CD89 (FcaRI), resulting in chronic inflammation and tissue damage. IgA (auto)antibodies and neutrophils are key players in various diseases, including blistering skin diseases and rheumatoid arthritis. Therefore, we generated an array of anti-CD89 monoclonal antibodies (mAbs) for therapeutic targeting of CD89. The biological activity of newly developed anti-human CD89 mAbs and their potential therapeutic capacity were investigated.MethodsHuman neutrophils were isolated from heparinized healthy donor blood. The ability of anti-CD89 mAbs to bind human neutrophils was investigated by flow cytometry. Furthermore, the capacity of these anti-CD89 mAbs to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and migration was studied. To this end, neutrophils were pre-incubated with/without anti-CD89 mAbs after which they were stimulated with IgA-coated beads. The amount of phagocytosed beads, NET release and migrated neutrophils were subsequently analysed. In parallel, chemoattractant leukotriene B4 and lactoferrin (as a measure for degranulation) release were determined. Finally, the therapeutic potential of our prototypic anti-CD89 mAb clone 10E7 was in vivo tested in anti-mouse collagen XVII human IgA-treated transgenic CD89 mice, a preclinical model for autoimmune linear IgA bullous disease (LABD).ResultsOur results show that all generated anti-CD89 mAbs bound surface CD89 on neutrophils. Although these anti-CD89 mAbs bind to different epitopes on EC1 of CD89, they all have the capacity to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and neutrophil migration. Moreover, IgA mediated leukotriene B4 and lactoferrin release are decreased in supernatant from anti-CD89 mAbs-treated neutrophils. Finally, anti-CD89 mAb clone 10E7, that was selected based on its selective binding profile on tissue micro arrays, reduced anti-mouse collagen XVII hIgA-induced neutrophil influx in an in vivo linear IgA bullous disease (LABD) mice model.ConclusionThis study clearly indicates that our newly developed anti-CD89 mAbs inhibited IgA-induced neutrophil activation and reduced anti-autoantigen IgA-induced neutrophil influx in vivo, supporting further clinical development for the treatment of LABD.

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Therapeutic exploitation of neutrophils to fight cancer

Cited by 21 publications

References 143 publications

Neutrophils as immune effector cells in antibody therapy in cancer

Neutrophils as immune effector cells in antibody therapy in cancer

Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis

Antagonizing FcαR1 (CD89) as treatment in IgA-mediated chronic inflammation and autoimmunity

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