IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

Abstract

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.

Clinical and Translational Significance of Basophils in Patients with Cancer

“…This can create localized immune cell activation and release of cytokines, histamine, and other tumor toxic factors which can prevent cancer growth and spread. These attributes of IgE and its ability to activate immune cells towards activated phenotypes and to restrict tumor growth have been investigated in several models of cancer by our group and others [109][110][111][112][113]. The MOv18 IgE trial has hailed the first-in-class IgE antibody, which is tested in a first-in-human phase I clinical trial at Guy's Hospital, London, and three other trial centers in the U.K.…”

In vivo trafficking of a tumor-targeting IgE antibody: molecular imaging demonstrates rapid hepatobiliary clearance compared to IgG counterpart

“…While a detailed investigation of the immunological mechanisms underlying the effects of anti-CSPG4 IgE was not the objective of the present study, it was previously demonstrated that IgE signaling could recruit and activate macrophages through a TNFα/MCP-1 pathway to adopt a pro-inflammatory, anti-tumoral phenotype, alongside triggering immune signaling pathways signifying parasite clearance rather than allergic response. 15 , 16 , 52 , 53 Importantly, we have shown that a human/mouse chimeric IgE did not cause basophil degranulation in blood samples from cancer patients, 34 , 54 and that the rat anti-CSPG4 IgE was shown to be safe in an immunocompetent rat model. 48 …”

IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer

“…The promising research on the role of IgE in cancer has led to the establishment of the emerging field of AllergoOncology, investigating multifaceted functions of IgE in cancer [27,28]. Interestingly, IgE may reprogram monocytes and macrophages toward cytotoxic functions, 7,41 and the first therapeutic application of tumor-specific IgE antibody MOv18 in ovarian cancer patients is presently ongoing in a registered clinical trial (NCT02546921). Overall, we provide evidence for a detrimental role of IgG4 in CRC from combined in vitro and patient-derived phenotypic and functional evaluations.…”