Abstract
Simple SummaryWhen activated by tumour antigen-specific IgEs, monocytes may contribute to the restriction of cancer growth in animal models of cancer. In this study, we investigated the effects of IgE stimulation on the activation state of human monocytes from healthy subjects and from patients with cancer. Cross-linking of cognate Fc receptors by IgE on human monocytes potentiated: (a) upregulation of activatory and down regulation of regulatory monocyte cell surface markers; (b) phosphorylation of intracellular protein kinases in monocytes previously described to be downstream of the mast cell and basophil FcεRI signalling pathway; (c) ovarian cancer patient monocyte-mediated cytotoxic killing of tumour cells and release of pro-inflammatory mediators, potentially associated with favourable patient survival. IgE can therefore activate human monocytes to acquire a pro-inflammatory phenotype capable of mediating effector functions against tumour cells. This may contribute to the mechanism of cancer immunotherapy using IgE antibodies.IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer.
Highlights
Monocytes engender multiple roles in homeostatic and disease processes, including in tissue repair [1], allergic inflammation [2], and bacterial and parasite infection clearance [3,4,5]
We evaluated whether IgE cross-linking on human monocytes could influence cell surface expression of markers of classical and alternative immune activation (Figure 1C)
Monocytes derived from healthy volunteers were either untreated or incubated with anti-tumour MOv18 IgE
Summary
Monocytes engender multiple roles in homeostatic and disease processes, including in tissue repair [1], allergic inflammation [2], and bacterial and parasite infection clearance [3,4,5] They reportedly exert pro- and anti-tumour functions [6]. These include IgE’s high affinity for cognate Fc receptors (FcεRs) (2 to 5-fold greater than IgG affinity for FcγRs) [11] and strong retention by FcεR-expressing immune effector cells, including mast cells, basophils, eosinophils, dendritic cells, monocytes and macrophages [9,11,12,13,14,15,16,17,18,19,20]
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