IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural states.
Antigens, Neoplasm
/ immunology
Biomarkers
Cytokines
/ metabolism
Cytotoxicity, Immunologic
Gene Expression
Humans
Immunoglobulin E
/ immunology
Inflammation Mediators
/ metabolism
Macrophage Activation
/ immunology
Macrophages
/ immunology
Models, Biological
Monocytes
/ immunology
Neoplasms
/ immunology
Phagocytosis
/ genetics
Prognosis
Protein Binding
/ immunology
Receptors, IgE
/ metabolism
Signal Transduction
AllergoOncology
Alternatively-activated macrophages
Cancer immunotherapy
IgE
Macrophages
Pellizzari et al.
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
13
02
2019
revised:
26
03
2019
accepted:
27
03
2019
pubmed:
9
4
2019
medline:
26
11
2019
entrez:
9
4
2019
Statut:
ppublish
Résumé
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. 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. A proportion (40%) of M2 and (<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. 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
A proportion (40%) of M2 and (<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
CONCLUSIONS
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.
Identifiants
pubmed: 30956175
pii: S2352-3964(19)30225-7
doi: 10.1016/j.ebiom.2019.03.080
pmc: PMC6562024
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
Biomarkers
0
Cytokines
0
Inflammation Mediators
0
Receptors, IgE
0
Immunoglobulin E
37341-29-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
67-81Subventions
Organisme : Medical Research Council
ID : MR/L023091/1
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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