How do cancer cells evade the body’s immune system?

An interdisciplinary team of scientists at the University of Iceland, Landspítali University Hospital and the University of Oslo have conducted a study that improves our understanding of how cancer cells avoid being killed by immune cells. The research is specifically focused on melanoma cells and has demonstrated the processes they use to defend themselves against the body’s immune response. The team has published three papers and their findings could improve the methods used to evaluate which patients are likely to respond to certain cancer treatments. The research is part of the doctoral project of Teitur Sævarsson, a PhD student in medical life sciences at the UI Faculty of Medicine. His supervisor is Berglind Ósk Einarsdóttir, senior lecturer at the same Faculty.

“The immune system is the body’s first line of defence against malignant cancer cells forming tumours. It is likely that malignant cells form in all our bodies many times over the course of our lives, but thanks to our immune cells they generally don’t survive to form tumours. Still, one in three people will be diagnosed with cancer at some point in their lives and this led us to think about why our immune cells don’t successfully recognise and kill all cancer cells,” explains Berglind.

Cancer cells are able to adapt and change their phenotypes to survive in hostile environments, for example when attacked by immune cells. “This adaptability is due to the large number of mutations that have accumulated in the DNA of the cancer cells. Natural selection means that the cells that are most successful in evading the immune response are the ones that survive and form tumours. So we can conclude that in cases where cancer cells do form tumours, they have found a way to get past the immune response and that is the process we are studying,” says Teitur.

Watching the fight between cancer cells and T-cells live

The study looks at melanoma cell lines from both humans and mice, cultured in plastic dishes in an incubator. “We genetically modify these cells to induce phenotypic changes similar to those that occur in real tumours. Then we use specific methods from molecular biology to analyse changes in the cells’ gene and protein expression. Finally we culture these melanoma cells together with immune cells, specifically T-cells. These co-cultures are carried out in a special imaging device that takes pictures of the cells every few hours. This enables us to watch the immune cells killing cancer cells in real time, so we can analyse which phenotypic changes affect the T-cells’ ability to kill cancer cells,” says Berglind.

The team is interdisciplinary in nature, since the study involves two major fields of research: cancer biology and immunology. “We have already published three papers exploring the ways in which cancer cells can bypass the immune response: two research papers and one systematic review,” says Teitur. The review paper compares the findings of almost 60 comparable experiments that have been published in international scientific journals.

Findings could be used to improve assessment of treatment options

The findings of this study shed light on the processes by which cancer cells can avoid being killed by immune cells. “We can see that when melanoma cells, which are generally differentiated cells, change phenotype and become undifferentiated, they become more sensitive to the signalling molecules secreted by immune cells. This leads to the cancer cells increasing the expression of genes and proteins whose function is to inhibit the ability of T-cells to kill them,” explains Berglind, referring to the findings of the first research paper.

The team’s second research paper further demonstrates that the changes that occur in the cancer cells, enabling them to evade the immune response, are largely due to the reprogramming of epigenetic modifications. “Epigenetic modifications are changes that affect gene activity without altering the genetic material itself. They control which genes are expressed and under what conditions, so they play an important role in cell development and activity. Cancer cells can use these modifications to change phenotype, adapt to their environment and thereby survive attacks from immune cells. Our findings suggest that epigenetic modifications play a key role in the phenotypic changes that we are researching,” adds Berglind.

One of the proteins that the scientists have observed cancer cells expressing when they change phenotype is the surface protein PD-L1. This protein has been extensively studied and is important for immunostimulatory cancer treatments, which have been used for over a decade and have changed the way we treat many kinds of cancer, including lung cancer and melanoma. Immunotherapy has become a key weapon in our arsenal against cancer but, as is often the case with chemotherapy, not all patients respond to the treatment. It is important to understand why this is and how we can predict patient responses. “Our findings provide a clearer picture of the conditions under which melanoma cells express high levels of PD-L1 and the biological processes behind that. This could help improve the methods used to evaluate which patients are likely to respond to immunotherapy and which are not,” says Teitur.

Research is essential for new treatments and diagnostic methods

Interdisciplinary studies like this have significant value for both the scientific community and society as a whole. “The scientific value lies in increased knowledge of the initial stages of tumour formation, as well as a better understanding of the conditions under which cancer cells express the PD-L1 protein, which is important when it comes to treatment decisions. The project also has value for society as a whole, as cancer is a disease that affects most people throughout their lives, directly or indirectly. Studies like this are essential for the development of new treatments and diagnostic methods that can improve the life expectancy and quality of life of people diagnosed with cancer. Projects like this also create opportunities to train the next generation of scientists, and numerous undergraduate and graduate students have worked with us on this project,” they say.

The study is a collaborative project between staff at the UI Faculty of Medicine, the Department of Immunology at Landspítali University Hospital, and the University of Oslo. As well as Berglind and Teitur, others who have contributed to the study include Siggeir Fannar Brynjólfsson, senior lecturer, Eiríkur Steingrímsson, professor, and Sólrún Melkorka Maggadóttir, lecturer and immunologist.

“Studies like this would not be possible without the development of the UI and Landspítali Biomedical Centre. In recent years, the Centre has built up a wealth of knowledge and secured access to important equipment, thanks to the tireless work of scientists at UI and Landspítali who, despite underfunding, have performed incredible feats to advance science in Iceland,” says Berglind.

The study is funded by the Icelandic Centre for Research (Rannís), the Icelandic Cancer Society’s Research Fund and the UI Doctoral Funds.

The three articles can be accessed by clicking the links below:

Differentiation status determines the effects of IFNγ on the expression of PD-L1 and immunomodulatory genes in melanoma

Enhanced IFNy response in dedifferentiated melanoma cells is due to chromatin remodeling as revealed by ATAC-seq

Differentiation state affects PD-L1 expression in cutaneous melanoma: a systematic review