Now we know why successful treatment does not affect specific cancer cells

Immunotherapy is a medical success story, as it enables doctors to treat and sometimes even cure cancers that used to be fatal. 

This does not apply to all cancers, though. The aggressive brain cancer glioblastoma fights back. And up until now, researchers did not know why. So says one of the researchers behind a new study from the University of Copenhagen.

“By mutating – that is, changing their DNA – cancer cells can become treatment resistant. However, glioblastoma tumour cells behave differently when subjected to immunotherapy,” says Clinical Professor and Team Lead at the Biotech Research and Innovation Centre (BRIC) Joachim Lütken Weischenfeldt, whose new study, published in Neuro-Oncology, describes tumour cells’ response to immunotherapy.

Glioblastoma is the most aggressive type of brain tumour found in adults with short-term survival. So we desperately need new, effective treatment methods

Every year, around 300 Danes are diagnosed with the rare cancer glioblastoma.

“By examining and comparing tumour material from before and after treatment with immunotherapy we were able to identify a group of patients in whom the appearance of the tumour cells had changed. The cells had simply put on a different ‘overcoat’,” Joachim Lütken Weischenfeldt explains.

Instead of mutating – an often lengthy process that requires changing the cell’s DNA – the tumour cells simply changed the way they look and behave.

“These cells – being able to change their appearance and resemble a particular type of cells found in bone marrow – are extremely plastic,” Joachim Lütken Weischenfeldt explains and adds:

“But the cancer cells were not the only cells to undergo change. We also saw significant changes in the macrophages and T-cells that surround and usually help kill the cancer cells.”

Untreated, cancer cells are usually able to protect themselves from T-cell attack. Immunotherapy prevents them from doing so.

“In the glioblastoma patients, immunotherapy didn’t render the cancer cells unable to protect themselves from T-cell attack. Our results suggest that they are able to assail the T-cells with signals and thus ‘exhaust’ them.”

In other words, glioblastoma cancer cells are able to circumvent immunotherapy by changing their appearance, rendering the treatment ineffective, and to protect themselves from T-cell attack by exhausting the T-cells.

This combination makes glioblastoma cancer resistant to immunotherapy and the body’s natural defence mechanisms, and this makes it a very aggressive type of cancer.

Rare, but fatal type of cancer

“Glioblastoma is the most aggressive type of brain tumour found in adults with short-term survival. So we desperately need new, effective treatment methods,” says Joachim Lütken Weischenfeldt.

He hopes the new study will pave the way for new treatment capable of fighting the glioblastoma cancer’s unique resistance mechanisms.

“When these tumour cells change their appearance, they express various proteins. And as these proteins will be unique to these cells, it should be possible to target them,” he concludes.

This would mean using the glioblastoma cancer’s tricky defence mechanisms against it. It will be a while before such treatment is available to patients, though.

“Developing treatment that only targets a specific type of cancer cell is tricky. So, it will take some time before we have found the right balance and are able to fight the tumour without causing major side effects,” Joachim Lütken Weischenfeldt explains.

The next step for Joachim Lütken Weischenfeldt and his colleagues is to try to identify other plastic cancers, where treatment failure cannot be fully attributed to genetic mutations.

“Conceptually, this study proposes a different approach to cancer treatment. The idea is to target the cancer cells’ plasticity, that is, their ability to change their appearance and interact with surrounding cells, including T-cells and macrophages. This could be the first step towards a more customised form of treatment for patients with aggressive cancers like glioblastoma for which we desperately need new treatment methods.”

Read the full study, “Immunotherapy drives mesenchymal tumour cell state shift and TME immune response in glioblastoma patients”, in Neuro-Oncology.

Contact

Clinical Professor and Group Leader Joachim Lütken Weischenfeldt
Joachim.Weischenfeldt@bric.ku.dk
+4535456040

Journalist and Press Consultant Liva Polack
liva.polack@sund.ku.dk
+4535325464