Researchers from departments including DTU Vet have made a ground-breaking discovery that enhances our understanding of how our immune system can exploit the genetic complexity of cancerous growths, even when the disease is far advanced. Their findings—which may prove crucial to future treatment involving immunotherapy—have recently been published in the respected journal Science.
A great many people have hailed immunotherapy as the greatest breakthrough in the past 30 years of cancer research. It entails attempting to stimulate the body’s immune system to attack cancer cells—in exactly the same way it tackles viruses and harmful bacteria for us every single day.
However, cancer cells have the capacity to conceal themselves from the body’s immune system, which enables them to develop undisturbed. Immunotherapy thus has to do with identifying the specific parts of the immune system that are able to attack cancer cells, and helping them to do so. Some patients benefit from the treatments that have already been developed within the field. Others do not. And now we know why.
“We’re able to measure how the immune system recognizes cancer cells,” explains Sine Reker Hadrup, Associate Professor at DTU Vet and one of the authors of the new study.
“We’ve analysed the immune system in selected patients, focusing on how their immune cells recognize mutations in the cancer cells. And here we can see that the immune system primarily reacts to what are known as clonal antigens, which is another name for the ‘trunk’ in the cancer cell,” she says.
Complex mutations
From a genetic perspective, a cancerous growth is extremely complex, because as the cells develop, numerous different antigens appear in different parts of the tumour itself—particularly in types of cancer that feature numerous mutations, such as lung cancer and melanomas. However, the earliest mutations are to be found in all cancer cells, and they therefore constitute the ‘trunk’ of the disease.
"We’re closer to hitting the centre of the target, but the challenge is that every treatment will have to be individualized for the patient in question."
Sine Reker Hadrup, Associate Professor at DTU Vet
Subsequent mutations appear in some—but not all—cells. The immune system is unable to recognize and attack mutations in these ‘branches’ in the same way. In fact, the new study indicates that chemo- and radiation therapy may even stimulate the development of additional mutations in the ‘branches’, which can grow back once more once the treatment has been completed.
“In other words, it would be a huge advantage if we could target the clonal cancer cells in the trunk. Firstly, because that is where we can hit the cells that are of the greatest significance to our survival, and secondly because it will enable us to limit the development of mutations in other parts of the tumour, thus preventing relapses,” explains Sine Reker Hadrup.
Activating the T-cells
In the laboratories, the researchers succeeded in isolating specialized immune cells—called ‘T-cells’—from samples taken from two patients with lung cancer. These T-cells were able to identify mutations that exist in all the patient’s cancer cells. Even though they have the potential to kill all the cancer cells, the cancer’s own defence mechanism deactivates them in the body. However, in combination with medication to obstruct the cancer cells’ defence mechanism, the study paves the way for treatments with the capacity to activate the T-cells so as to target all the cancer cells at the same time.
“Our goal is to prepare targeted immunotherapy strategies where we encourage the immune system to attack the specific parts cancer cells that are crucial to destroying the tumour. We have now taken a big step towards understanding which elements we need to target with these attacks,” adds Sine Reker Hadrup.
Targeted attack
In the future, researchers may potentially utilize this property by harvesting and cultivating T-cells that can recognize the common antigens and then reintroducing them into the patient’s body to help the patient’s own immune system to combat the cancer.
“We’re closer to hitting the centre of the target, but the challenge is that every treatment will have to be individualized for the patient in question,” says Sine Reker Hadrup.
“This is because the mutations vary from one patient to the next, and not all patients currently benefit from immunotherapy. However, for every patient in this study, we were able to identify around 100 mutations where there are fragments which the immune system may possibly be able to recognize. That is great news, because we know that the immune system can be really effective in wiping out cancer cells. And when we succeed in finding these specific T-cells in patients, we can take them out, cultivate them and then reintroduce them into the patients where they can carry out targeted attacks on precisely that patient’s cancer cells,” concludes Sine Reker Hadrup.
The findings have just been published in Science.
Watch the video from Cancer Research UK: