IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural statesResearch in context

Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associate...

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Published in:EBioMedicine 2019-05, Vol.43, p.67-81
Main Authors: Giulia Pellizzari, Coran Hoskin, Silvia Crescioli, Silvia Mele, Jelena Gotovina, Giulia Chiaruttini, Rodolfo Bianchini, Kristina Ilieva, Heather J. Bax, Sophie Papa, Katie E. Lacy, Erika Jensen-Jarolim, Sophia Tsoka, Debra H. Josephs, James F. Spicer, Sophia N. Karagiannis
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container_issue
container_start_page 67
container_title EBioMedicine
container_volume 43
creator Giulia Pellizzari
Coran Hoskin
Silvia Crescioli
Silvia Mele
Jelena Gotovina
Giulia Chiaruttini
Rodolfo Bianchini
Kristina Ilieva
Heather J. Bax
Sophie Papa
Katie E. Lacy
Erika Jensen-Jarolim
Sophia Tsoka
Debra H. Josephs
James F. Spicer
Sophia N. Karagiannis
description Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation. Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells. Findings: A proportion (40%) of M2 and (
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Bax ; Sophie Papa ; Katie E. Lacy ; Erika Jensen-Jarolim ; Sophia Tsoka ; Debra H. Josephs ; James F. Spicer ; Sophia N. Karagiannis</creator><creatorcontrib>Giulia Pellizzari ; Coran Hoskin ; Silvia Crescioli ; Silvia Mele ; Jelena Gotovina ; Giulia Chiaruttini ; Rodolfo Bianchini ; Kristina Ilieva ; Heather J. Bax ; Sophie Papa ; Katie E. Lacy ; Erika Jensen-Jarolim ; Sophia Tsoka ; Debra H. Josephs ; James F. Spicer ; Sophia N. Karagiannis</creatorcontrib><description>Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation. Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells. Findings: A proportion (40%) of M2 and (&lt;20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. IgE crosslinking enhanced the FcεRI-dependent signalling pathway, including phosphorylation of the Lyn kinase, ERK1/2 and p38 in M2 macrophages and upregulated Lyn gene expression by M1 and M2 macrophages. Anti-tumour IgE engendered ADCC of cancer cells by all macrophage subsets. Interpretation: IgE can engage and re-educate alternatively-activated macrophages towards pro-inflammatory phenotypes and prime all subsets to mediate anti-tumour functions. This points to IgE-mediated cascades with potential to activate immune stroma and may be significant in the clinical development of strategies targeting tumour-resident macrophages. 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Bax</creatorcontrib><creatorcontrib>Sophie Papa</creatorcontrib><creatorcontrib>Katie E. Lacy</creatorcontrib><creatorcontrib>Erika Jensen-Jarolim</creatorcontrib><creatorcontrib>Sophia Tsoka</creatorcontrib><creatorcontrib>Debra H. Josephs</creatorcontrib><creatorcontrib>James F. Spicer</creatorcontrib><creatorcontrib>Sophia N. Karagiannis</creatorcontrib><title>IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural statesResearch in context</title><title>EBioMedicine</title><description>Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation. Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells. Findings: A proportion (40%) of M2 and (&lt;20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. IgE crosslinking enhanced the FcεRI-dependent signalling pathway, including phosphorylation of the Lyn kinase, ERK1/2 and p38 in M2 macrophages and upregulated Lyn gene expression by M1 and M2 macrophages. Anti-tumour IgE engendered ADCC of cancer cells by all macrophage subsets. Interpretation: IgE can engage and re-educate alternatively-activated macrophages towards pro-inflammatory phenotypes and prime all subsets to mediate anti-tumour functions. This points to IgE-mediated cascades with potential to activate immune stroma and may be significant in the clinical development of strategies targeting tumour-resident macrophages. 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Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells. Findings: A proportion (40%) of M2 and (&lt;20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. 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title IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural statesResearch in context
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