Immunotherapy can be highly effective against cancer, but not all patients benefit from it. Only a small number of breast cancer patients benefit from this type of treatment, which turns the patient's own immune system against the tumor. And if the majority of doctors had had a say in it, the treatment wouldn't even have been tested in this patient group. "The immune system wasn’t believed to play a role in breast cancer, so they assumed it wouldn't work," says medical oncologist and researcher Marleen Kok from the Netherlands Cancer Institute.
Nevertheless, she was the first in the Netherlands to initiate a trial using immunotherapy for breast cancer patients in 2015. “That required a lot of perseverance because no one was in agreement about this. You can’t let that deter you,” Kok explains, her expression radiant when remembering the first hopeful signals about the participating patients.
Her research showed that immunotherapy can be effective in some breast cancer patients. The question is: how does this immune response against cancer work, and why do some patients respond while others don’t? To find out more, she structurally collaborates with fundamental researcher and group leader Karin de Visser from the Netherlands Cancer Institute and Oncode Institute. For years they analyzed the well-known immune cells called T cells, although their primary focus was on the lesser-known types. They discovered that a rare immune cell may be of crucial importance.
They found an unexpected actor: eosinophils. “We know this type of immune cell from allergies and the immune response against parasites,” De Visser explains. “Cancer researchers often overlook it.” And now these cells appear to play an essential role in the working of immunotherapy.
The research team analyzed blood samples of patients with breast cancer who responded well to immunotherapy. They appeared to have an increased eosinophil count. “This surprised us,” Kok explains. “We wondered whether this was an effect of the immunotherapy, or whether it was essential to the efficacy of the therapy. We could only interpret the importance of this finding once we had thoroughly investigated it in mice.”
“Our mice with breast cancer seem to be a very good model for the reality in our patients,” De Visser explains. “The mice that respond well to immunotherapy create more eosinophils, just like humans. It’s quite eye-opening to see how well they resemble patients, also for our colleagues to whom we present our work. Additionally, removing eosinophils is an option in mice, but not in humans. Mice that don’t have eosinophils don’t show a response to immunotherapy anymore. This shows that these cells are important in successful treatment with immunotherapy.”
How could this eventually help patients with breast cancer? As it turns out, eosinophils activate other immune cells (T cells) that in turn destroy cancer cells. This would allow you to enable the immune system of a patient with breast cancer indirectly, or so the researchers predict. “We are currently investigating whether eosinophils could help us improve immunotherapy results in the future.” De Visser: “We have partly been able to do so in our mouse models.”
If you want to study these cells, you do need to face a new reality. “Our team members always carried their pagers with them in case blood or tissue from a patient would come in,” De Visser shares. “You can only study eosinophils in fresh blood or tissue. They won’t survive if you freeze them, as opposed to many other cells. So we had to have a team ready to analyze body materials from patients at all times. One group member even returned from holiday to analyze the blood of a patient who responded exceptionally well to immunotherapy.”
The researchers explored new territory in another area as well: the integration of patient trials and fundamental research at the lab. They went back and forth between mouse and human to verify that what was found in one also worked in the other. "This interplay between the clinic and the lab is unique and led our research in a completely new direction," says De Visser.
“We were investigating a different type of immune cell at first, neutrophils”, De Visser explains. “But in patients as well as in mice with breast cancer, we witnessed the unexpected increase in eosinophil count. You need to keep an open mind when looking at your results, and follow up on any unexpected findings.”
A challenging course, in which success was not guaranteed. It’s no surprise that the researchers were given a unique high-risk grant from KWF Dutch Cancer Society. It does not stop them from pioneering further. And tunnel vision is still out of the question because a vial of patient blood with its millions of cells most likely contains much more new information. Kok: “We like to be surprised by the unknown. That’s the only way to advance in science and develop better immunotherapy for cancer patients.”
This research was financially supported by KWF Dutch Cancer Society and Oncode Institute