IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural states

TY - JOUR

T1 - IgE re-programs alternatively-activated human macrophages towards pro-inflammatory anti-tumoural states

AU - Pellizzari, Giulia

AU - Hoskin, Coran Michael

AU - Crescioli, Silvia

AU - Mele, Silvia

AU - Gotovina, Jelena

AU - Chiaruttini, Giulia

AU - Bianchini, Rodolfo

AU - Ilieva, Kristina Maksimova

AU - Bax, Heather Jane

AU - Papa, Sophie Elinor

AU - Lacy, Katie E.

AU - Jensen-Jarolim, Erika

AU - Tsoka, Sophia

AU - Josephs, Debra Hannah

AU - Spicer, James Frederick

AU - Karagiannis, Sophia N

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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 (<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.

AB - 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 (<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.

KW - AllergoOncology

KW - Alternatively-activated macrophages

KW - Cancer immunotherapy

KW - IgE

KW - Macrophages

KW - Pellizzari et al.

UR - http://www.scopus.com/inward/record.url?scp=85063907844&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.03.080

DO - 10.1016/j.ebiom.2019.03.080

M3 - Article

SN - 2352-3964

VL - 43

SP - 67

EP - 81

JO - EBioMedicine

JF - EBioMedicine

M1 - EBIOM2073

ER -