The Surprising Connection Between Cancer and Allergy
Could the same antibody that triggers allergies protect against tumors?
IgE, a key indicator of allergic diseases, is increasingly recognized for its potential role in tumor immunity.
The allergic antibody IgE
Immunoglobulin E (IgE) is evolutionarily thought to play a role in immune responses against parasitic infections, but its pathophysiology is associated with the development of allergies. Detecting serum IgE specific to an allergen is the primary determinant of allergy. IgE produced by plasma cells binds to its canonical receptor FCεR1 on mast cells and basophils, priming them for antigen re-exposure.
Once re-exposed to an antigen, such as pollen, dust mites, insect stings or certain foods, a rapid onset of symptoms may occur, such as redness, itching, swelling, difficulty breathing or anaphylaxis. While the importance of IgE in allergy is understood, there is growing interest in understanding how allergic disease may relate to cancers.
The link between IgE, allergy and cancer
The relationship between IgE, allergy and cancer has been reported as early as the 1960s, with studies finding a decreased risk of cancer associated with atopy and the presence of serum IgE.
Chronic inflammation hypothesis
Allergic inflammation promotes cancer risk by inducing oxidative damage, tissue remodeling and mutations at inflammation sites. For example, a study by Hayes et al. demonstrated that chronic skin inflammation in mice increases IgE levels, leading to basophil recruitment and epithelial hyperplasia. This inflammatory environment promotes the growth of precancerous epithelial cells with oncogenic mutations, supporting the link between chronic allergic inflammation and cancer risk, such as non-melanoma skin cancers in atopic dermatitis patients.2
Immunosurveillance hypothesis
Allergies may enhance immune responsiveness, aiding in detecting and eliminating precancerous cells. High serum IgE levels correlate with reduced cancer risks, supported by data showing IgE-driven activation of effector cells targeting tumors. For example, patient samples, including blood and tissue biopsies, showed that IgE antibodies targeting tumor antigens like HER2 restricted tumor growth more effectively than IgG antibodies.3 This study gives insight into the role of IgE in activating immune cells like macrophages and eosinophils to enhance tumor immunosurveillance.
Prophylaxis hypothesis
Allergic symptoms such as sneezing or coughing may expel carcinogens, reducing cancer risk. This protective effect is thought to occur because allergy symptoms like coughing and sneezing help expel potential carcinogens before they can damage tissues or initiate carcinogenesis.4 Liao and colleagues found that individuals with respiratory allergies show a lower risk of head and neck cancers, giving some validity to this hypothesis.5
Th2 skewing hypothesis
Th2 immune responses (the allergic response) may suppress the anti-tumoral Th1 response, creating an environment favorable for cancer development at the site of inflammation. An example of this would be asthma increasing lung cancer susceptibility. To support this theory, Frafjord and colleagues showed that non-small cell lung cancer is predominantly infiltrated by Th2 and regulatory T cells, with minimal Th1 immune response.6 This Th2-skewed immune environment suppresses anti-tumor immunity, subsequently allowing tumor progression.
Allergic antibodies as an immunotherapy
The immunosurveillance hypothesis brings into consideration the idea of using allergic antibodies as an immunotherapy. IgG1 antibodies are the primary class of monoclonal antibodies produced as cancer immunotherapies. These antibodies are known for their strong activation of Fcγ receptors (FcγRs) and are used in therapies that trigger immune-mediated effects leading to tumor cell killing. However, IgE has gained traction as an alternative therapeutic to the traditional IgG-based immunotherapy as IgE exhibits tissue presence and potent effector activation, which have been hypothesized to offer distinct advantages in cancer therapy.7 These properties enable IgE to engage tumor-resident immune cells, such as macrophages and mast cells, to orchestrate anti-tumoral responses. These responses are based on mechanisms that IgG-based therapies cannot engage through interfacing with FcγRs, making IgE a promising novel candidate for cancer immunotherapies as a standalone or combination therapy with conventional IgG-based therapy.
How might IgE engage tumors differently? IgE antibodies exhibit a high affinity for their canonical receptor FcεRI with two to three orders of magnitude stronger binding than IgG to FcγRs.
The IgE-FcεRI complex, once activated, triggers degranulation and cytokine release, leading to inflammatory cell recruitment to the tumor microenvironment (TME). Additionally, IgE-primed immune cells mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) through the lower affinity receptor FCεRII (CD23).
Immune cells may release toxic mediators like nitric oxide and TNFα. These mechanisms enhance tumor antigen presentation by antigen-presenting cells like dendritic cells and macrophages, priming adaptive T-cell responses. Taken together, these attributes make IgE a promising therapeutic candidate for cancer immunotherapy.
IgE as a cancer biomarker
While higher levels of serum IgE have been associated with allergic disease, ultra-low levels of IgE have been identified as a potential biomarker for cancer due to its association with increased risk for tumor malignancies. Epidemiological studies have shown that individuals with low or absent IgE levels are at a higher risk of developing malignancies compared to those with normal or elevated IgE levels.10
Moreover, the absence of IgE may indicate impaired tumor immunosurveillance. This may suggest that ultra-low serum IgE levels may serve as a marker for cancer susceptibility. The exact mechanisms underlying this association remain unclear, and it is not yet known whether low IgE levels are a cause or consequence of cancer or whether it reflects a broader immune dysregulation.
Where is the field of allergooncology going?
The field that unifies the study of allergy and cancer is very new. There are many unknowns: IgE may play a positive or negative role in cancer, and its role may be specific to different cancer types. Indeed, as research progresses on IgE's role, it may open avenues for novel cancer therapies as a method of immunosurveillance. IgE-based treatments could complement or surpass traditional IgG therapies in certain malignancies with their long tissue residence, directed tumor killing, and repolarization of macrophages towards ADCP. The use of IgE as a biomarker may also give insight into cancer progression and survival – a recent study found a positive correlation between serum IgE levels and improved survival of patients with glioblastoma.
Altogether, the field of allergooncology is looking to understand how allergies may influence cancer progression, and future findings will help improve cancer survival and may open new avenues for treatment.
