By Tom Ulrich
Allergies of all kinds – to food, pollen, pets, etc. – can be blamed on a kind of antibody called IgE. Cousins of the more common IgG, IgE antibodies work with immune cells called mast cells to trigger the symptoms we associate with an allergic reaction (itchy skin, runny nose, closing throat, etc.).
Edda Fiebiger, PhD, has been studying IgE and allergies for years, and has noticed a curious association in several epidemiologic studies: people with high levels of IgE in their blood (as in people with allergies) have a lower risk of certain cancers. This – and the discovery of human IgE antibodies that bind to tumor antigens – suggests that IgE may help protect the body from cancer, and has given rise to a whole new field dubbed AllergoOncology.
But how does it work? In a recent paper in Cell Reports, Fiebiger and her colleagues reveal a pathway by which IgE may keep watch for tumor cells, one that’s totally separate from its allergic role.
The pathway, called antigen cross-presentation, relies on immune sentries called dendritic cells (DCs). DCs constantly sample and taste their surroundings, in part using receptors that latch onto IgG immune complexes – jumbles of IgG antibodies bound up with antigens.
When a DC grabs one of these IgG complexes, it absorbs it and displays – or “presents” – pieces of the antigen on its surface, alongside proteins that stimulate infection-fighting T-cells. The T-cells then seek out and destroy unhealthy cells carrying those same antigens.
Human DCs also have receptors for IgE, but they work a little differently. Instead of grabbing passing complexes of antibodies and antigens, the IgE receptors grab free IgE, coating the cell with it.
“At steady state, the dendritic cell is covered in IgE,” says Fiebiger, who works in Boston Children’s Hospital’s Division of Gastroenterology, Hepatology and Nutrition.. “It helps the dendritic cell sense antigens that are present only at low concentrations.” Like tumor antigens.
IgE then acts like a mousetrap, ready to nab passing antigens and pull them into the DC. What hasn’t been clear up to now, though, is whether DCs can use those antigens to turn on T-cells, like they do with antigens harvested from IgG immune complexes.
The answer, it turns out, is yes.
Like a cancer vaccine
Using mice engineered to produce human IgE receptors on their DCs (mouse DCs don’t have their own IgE receptors), Fiebiger’s team showed that IgE-coated DCs could grab, process and present ovalbumin (OVA), a classic model antigen. Those DCs could also activate T-cells primed to recognize OVA, even when only low amounts of the antigen were available.
What’s more, the same mechanism could trigger an immune attack against a tumor, Fiebiger’s team collected DCs from the engineered mice, loaded them with OVA-recognizing IgE, and treated them with a dose of the antigen. They then injected the OVA-presenting DCs back into the mice, along with OVA-producing tumor cells.
The injection acted like a cancer vaccine (a form of cancer immunotherapy that’s been studied for decades), slowing, and in some cases preventing, tumor formation in the treated mice. It also instilled immune memory in the mice, protecting them from additional injections of the same OVA-producing tumor cells some weeks later.
These data and those from other studies make Fiebiger and others think that IgE may be a kind of anti-tumor watchdog, sniffing around for tumor-related antigens and alerting the immune system to kill tumors before they get too big. “It’s probably happening all the time,” she muses.
Could this IgE-DC pathway have treatment potential? There are a number of antibody-based cancer therapies on the market now (e.g., trastuzumab [Herceptin®] for breast cancer, rituximab [Rituxan®] for leukemias and lymphomas). But they’re all based on IgG.
Fiebiger notes that at least one laboratory is working on what is essentially an IgE version of Herceptin.
“We’re not the ones who invented the idea that IgE plays a role in cancer,” she says. “But so far we’re the only ones to have found a good mechanism to explain it.”