Insights from IgE Immune Surveillance in Allergy and Cancer for Anti-Tumour IgE Treatments

Abstract

IgE, the predominant antibody class of the allergic response, is known for its roles in protecting against parasites; however, a growing body of evidence indicates a significant role for IgE and its associated effector cells in tumour immunosurveillance, highlighted by the field of AllergoOncology and the successes of the first-in-class IgE cancer therapeutic MOv18. Supporting this concept, substantial epidemiological data ascribe potential roles for IgE, allergy, and atopy in protecting against specific tumour types, with a corresponding increased cancer risk associated with IgE immunodeficiency. Here, we consider how epidemiological data in combination with functional data reveals a complex interplay of IgE and allergy with cancer, which cannot be explained solely by one of the existing conventional hypotheses. We furthermore discuss how, in turn, such data may be used to inform future therapeutic approaches, including the clinical management of different patient groups. With epidemiological findings highlighting several high-risk cancer types protected against by high IgE levels, it is possible that use of IgE-based therapeutics for a range of malignant indications may offer efficacy to complement that of established IgG-class antibodies.

Keywords: AllergoOncology; IgE; antibodies; cancer; immunotherapy.

Figure 1

IgE and IgE therapy-mediated cellular immune surveillance against cancer. Direct and cell-mediated effects of IgE against tumour cells (shown in brown). IgE is able to engage with a unique repertoire of effector cells via the IgE receptors Fcε receptor I (FcεRI) and CD23/FcεRII. These interactions can drive potentially anti-tumour functions, including antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP) and release of cytotoxic mediators. IgE engagement with monocytes and alternatively activated M2 macrophages can drive repolarisation to a M1-like classically activated phenotype, as well as increased macrophage recruitment to tumour sites. IgE can also contribute to antigen presentation via dendritic cells and B cells and activate both CD4 and CD8 T cells, further promoting a pro-inflammatory environment and tumour cytotoxicity.

Figure 2

The combinatorial hypothesis accounts for the complex relationship between allergic diseases and an individual’s risk of developing a specific cancer. The combinatorial hypothesis takes into account different immunological conditions created within the context of specific local and systemic allergic diseases, which influence the risk for the development of different cancer types. This risk may be derived from four hypotheses thus far proposed to explain the nature of the relationship between IgE, allergy/atopy, and cancer. These hypotheses can in turn be divided into those that propose an anti-tumour outcome and those proposing a pro-tumour outcome. For anti-tumour outcomes, the prophylaxis hypothesis assumes that symptoms of allergy, such as coughing and sneezing, act to expel potential carcinogens before they can trigger tissue damage and inflammation. Reported decreased risk of cancers of the upper gastrointestinal tract associated with respiratory allergy is an example in support of this hypothesis. The second anti-tumour hypothesis is the immunosurveillance hypothesis, which states that allergy is reflective of a hyperactive immune system, which in turn is better equipped to defend against tumours. Supporting this, several cancers distant to the site of allergic inflammation are protected against by presence of allergy or high serum IgE. The pro-tumour hypotheses are the chronic inflammation hypothesis and the Th2 skewing hypothesis. The chronic inflammation hypothesis presumes that inflammation, driven by allergy, drives mutation of regulatory growth and tumour-suppressor genes, can increase cancer risk at sites of allergic challenge. This hypothesis is supported by increased lung cancer risk associated with asthma and increased non-melanoma skin cancer risk associated with atopic dermatitis. The Th2 skewing hypothesis, presumes atopy and chronic exposure to allergen challenge may drive inappropriate skewing towards alternatively activated Th2-based immune response over potentially anti-tumour Th1 or away from the typical Th2 (IgE-driven) responses, leading to an increased cancer risk at sites affected by atopy.