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Disease and treatment

Danish researchers develop new type of immunotherapy

Danish researchers have discovered a new way of developing immunotherapy for cancer. Unlike current immunotherapy, which is only effective for about half the people with some types of cancer, this new type of immunotherapy may be effective on all types.

Immunotherapy has revolutionized cancer treatment in recent years and has saved an incredible number of lives. Nevertheless, current immunotherapy has some limitations, including only being effective for about half the people with some types of cancer.

However, a new immunotherapy method developed and patented by researchers from Aarhus University may revolutionize immunotherapy once again. In any case, experiments in mice show that this new immunotherapy is not only effective against the types of cancer that can be successfully treated with immunotherapy today but also against other types.

“Our immunotherapy differs from current clinical immunotherapy that targets T cells to boost the immune response. This is very effective for many people, but not for everyone. Instead of directly boosting the T cells that kill tumours, we remove the natural brakes in the immune system, triggering a strong immune response to cancer,” explains the first author, Anders Etzerodt, Assistant Professor, Department of Biomedicine, Aarhus University.

The research results were recently published in the Journal of Experimental Medicine.

Tumours exploit the body’s immune response

How does the immune system work?

The immune system comprises myriad cells, and the macrophages are the most interesting ones in this context. There are many types of macrophages. Some are aligned with the immune response that combats cancer, but tumours exploit the vast majority.

Some macrophages enable tumours to grow by helping to form new blood vessels to supply the tumours with nutrients; some macrophages suppress the immune system so that it does not go into overdrive in combating the cancer cells. These immunosuppressive macrophages were the focus of the research project.

“Tumours use the immunosuppressive macrophages to silence the immune system, thus disabling the body’s defences,” explains Anders Etzerodt.

Specific macrophages suppress the immune response to cancer

The immunosuppressive macrophages that have the CD163 antigen on the cell surface (CD163+ macrophages) are especially problematic for people with cancer.

CD163+ macrophages are present in many types of cancer, including skin cancer, lung cancer, colon cancer and pancreatic cancer. The more CD163+ macrophages people have in their tumours, the less likely they are to survive cancer.

Anders Etzerodt’s research on mice shows that the CD163+ macrophages prevent the immune system from attacking the tumours, regardless of the type of immunotherapy used.

Developing nanoparticles to penetrate tumours and disable the macrophages

Anders Etzerodt and colleagues have developed nanoparticles with antibodies that target CD163 on the cell surface.

The nanoparticles are lipid particles that are so tiny that they can penetrate from the bloodstream into the tumour tissue. However, they are also large enough that they cannot penetrate healthy tissue. However, the tissue in tumours is more permeable because the tumours need many nutrients to grow.

Once the nanoparticles enter the tumour tissue, they attach to the CD163+ macrophages and disable them.

“This is a very specific way to target very specific macrophages that play a role in developing cancer. Other researchers have tried to disable all the macrophages, but then they also eliminate the ones that are required for an effective immune response, including cancer, and then the tumour cells survive,” says Anders Etzerodt.

Mice killed because they lived too long

Anders Etzerodt and his colleagues tested their anti-CD163 immunotherapy on mice with skin cancer, pancreatic cancer and ovarian cancer.

The results show that this new immunotherapy can contribute to tumour regression in all cases, including cancer in which traditional immunotherapy, such as checkpoint inhibitors, is not effective.

The results were so convincing in mice that had pancreatic cancer that they survived for 20 weeks instead of the usual 10 weeks. This meant that the researchers had to kill the mice because they were not allowed to perform tests on mice that exceeded twice their life expectancy.

“After 20 weeks, none of the mice had become more ill. This is a very convincing result,” says Anders Etzerodt.

Removing the brakes from a car

Further studies on the mice revealed exactly how the immunotherapy worked.

After the CD163+ macrophages were destroyed in the tumours, the immunosuppressive response was disabled, and monocytes were mobilized into the tumours.

The monocytes have the potential to develop into many macrophage types, including those that are part of the immune response to cancer cells.

In addition, the researchers also found that the tumour tissue was filled with many T cells that drive the body’s response to tumours. Specifically, there was a massive infiltration of the CD8 T cells that destroy the tumour cells.

“The macrophages we disabled play a role in suppressing many of the immune system processes that usually destroy tumours. Disabling the macrophages is like removing the brakes on a car. This causes the immune system to go into overdrive until all tumour cells are destroyed,” says Anders Etzerodt.

Anders Etzerodt hopes that he can continue to develop this new form of immunotherapy. Investors are currently required to take the research to the next stage, and the researchers are in the process of finding the right collaborators.

Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression” has been published in the Journal of Experimental Medicine. In 2014, the Novo Nordisk Foundation awarded a grant to Anders Etzerodt for the project Investigation into the Role and Use of CD163 as a Therapeutic Target in Tumor-associated Macrophages.

Anders Etzerodt
PhD, Assistant Professor
Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti-PD-1 checkpoint therapy. Specific depletion of the CD163+ macrophages results in a massive infiltration of activated T cells and tumor regression. Importantly, the infiltration of cytotoxic T cells was accompanied by the mobilization of inflammatory monocytes that significantly contributed to tumor regression. Thus, the specific targeting of CD163+ TAMs reeducates the tumor immune microenvironment and promotes both myeloid and T cell-mediated antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells in a therapeutic context.