A type of immunotherapy which has undergone preliminary testing on mice shows promise for the future treatment of ovarian cancer, a cancer which is often discovered too late resulting in a high mortality rate. The research group behind the study is headed by Anders Etzerodt from the Department of Biomedicine at Aarhus University.

2020.03.26 | Nanna Jespersgård

We have gained a new and deeper understanding of what is helping and what is hindering the body in the development of ovarian cancer. I'm looking forward to testing this in clinical trials on patients who currently have a really poor prognosis, Anders Etzerodt says. Photo: Jann Thiele Zeiss, AU.

Malignant ovarian cancer is insidious: Known and feared for vague and uncharacteristic symptoms that often mean the disease is discovered so late that on average only four out of six patients are still alive after five years. Researchers from Aarhus University are hoping to change this situation in the future.

Together with research colleagues from France and the UK, they have published a study conducted in mice showing that it appears to be possible to hinder the spread of ovarian cancer and reduce the tumour by removing some specific immune cells, known as macrophages, from the fat that is stored in the abdominal cavity and hanging in front of the intestines. The omental fat, as it is known, became well-known a few years ago under the name ‘skinny fat’. However, it should not be confused with the layer of fat seen in overweight people as visible rolls of fat under the skin.

Visceral fat as a problematic host

Anders Etzerodt is PhD and assistant professor of cancer immunology at the Department of Biomedicine at Aarhus University. He is the lead author of the study, which has been published in the Journal of Experimental Medicine. He explains that ovarian cancer most often occurs in the fallopian tubes and that the starting point for the research project was familiar knowledge about cancer cells from this type of cancer being able to detach and shed into the abdominal cavity. Because this occurs very early in the course of the disease, the ‘homeless’ cancer cells need to fasten onto something to survive.

“This is where the omental fat becomes a kind of host for cells which would otherwise perish, and our research now shows that when tumour cells move into the omental fat, two specific types of immune cell known as macrophages alter character. They develop into the disease’s small supporters,” says Anders Etzerodt.

“One of the macrophage types which is already present in the tissue simply begins to help the tumour spread further to the other organs in the abdominal cavity. At the same time, the second type of macrophage, which comes from the bloodstream and is recruited as a reaction to the infiltration of tumour cells into the omental fat, begins to counteract the immune system’s attempt to fight the invasive cancer cells. In this way, they help the tumour to grow larger," says Anders Etzerodt about the new findings.

In the study, the researchers initially experimented with removing the macrophages already found in the tissue, which led them to establish that this inhibited the spread of cancer in the abdominal cavity – though without the tumour in the omental fat becoming smaller. When the researchers simultaneously removed the above-mentioned macrophages from the bloodstream, the result was both less spreading and a shrinking tumour.

Immunotherapy that 'puts the brakes on the brake'

"We describe a type of immunotherapy which differs from the immunotherapy that is characterised by supporting the T-cells that kill a tumour, and which has become an established part of modern immunological treatment," says Anders Etzerodt.

"What we’re doing is also immunotherapy, but it focuses on another part of the immune system. This project is only the third scientific article to describe how macrophages with different origins affect tumour development, and precisely how the macrophages that are found to inhibit the immune system’s ability to hamper the cancer can be removed. They ‘put the brakes on the brake’, if you will,” he explains.

Anders Etzerodt also explains that he and his colleagues found the new types of macrophages using a new technique called single-cell sequencing, a method which gives the researchers very detailed information about the processes that take place in each individual cell.

People are the next step

According to Anders Etzerodt, the research result has obvious potential for improved treatment in the future, though with the important proviso that the testing has only been conducted on mice so far. The next step is to develop a medicine which can be tested on people. According to Anders Etzerodt, this is particularly interesting because the research group has previously shown that similar macrophages from the bloodstream are also present in models for skin cancer.

"So far, we’ve gained a new and deeper understanding of what is helping and what is hindering the body in the development of ovarian cancer, and I'm looking forward to testing this in clinical trials on patients who currently have a really poor prognosis," he says.

Ovarian cancer – more information

• Ovarian cancer occurs in approximately 570 women in Denmark every year.
• The disease is the second most frequent type of pelvic cancer in Denmark (uterine cancer is the most frequent). Approximately eight times as many women get breast cancer.
• Ovarian cancer is difficult to detect, among other things because there are few or no symptoms in the beginning.
• As the tumour grows it can lead to stomach discomfort, and the stomach can become bigger and feel distended. Sometimes people think they have gained weight and try to lose it again. Others find that they need to empty their bladder more often, some people suffer constipation due to the pressure of the growing tumour on the surrounding organs, and some feel fatigued.
• Following a diagnosis of ovarian cancer, 74 per cent will be alive one year later and 38 per cent will be alive five years later. However, the prognosis is very dependent on the stage of the disease.
  Source: Sundhed.dk

The research results – more information

• The study is basic research in which the experimental trials were carried out on mice.
• The most important collaborative partner is Toby Lawrence, Lawrence Group at King’s College, London.
• The study is financed by the Novo Nordisk Foundation via a postdoc scholarship given to Anders Etzerodt for research abroad.
• With reference to possible conflicts of interest, Anders Etzerodt informs that if everything goes well, he plans a spinout company, but that it will focus on treatment of other types of cancer such as skin cancer and cancer of the pancreas.
• The article Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer has been published in the Journal of Experimental Medicine.

Contact

Assistant Professor of Cancer Immunology, PhD, Anders Etzerodt
Aarhus University, Department of Biomedicine
Mobile: (+45) 2812 8421
Email: ae@biomed.au.dk