Researchers have uncovered new details about the complex relationship between the immune system and cancer. They have shown that this relationship can influence the distribution and frequency of genetic mutations that promote the growth and spread of cancer. Tumours that can withstand the body’s attempt to destroy them – described as ‘escaping the immune system’ – have a higher number and broader range of mutated sites.
The study also revealed that people with these tumours had lower rates of survival than those whose tumours were subject to attack from the immune system. On this basis, the researchers suggest that the ‘escape status’ of a person’s tumour could be used in a clinical setting to help determine their likely outcome and, in turn, optimise their treatment.
Finally, the team identified associations between escaped tumours and mutational patterns known to develop through exposure to smoking and UV light. It is therefore possible that these exposures increase the cancer’s ability to evade the immune system.
The study was carried out by researchers at The Institute of Cancer Research, London, and University College London, with funding coming from Cancer Research UK, the Wellcome Trust and the National Institute of Health. The findings were published in the journal Genome Biology.
A complicated relationship
The relationship between cancer and the immune system is a complicated one. The immune system is designed to recognise cancerous cells as harmful because of the proteins they display on their surface, which immune cells identify as non-self. In the very early stages of cancer, immune cells can control tumour growth by killing cancerous cells. Even if the tumour’s growth rate increases, the immune system can often keep the disease in check, preventing it from spreading to other areas of the body.
Over time though, cancer cells can acquire genetic changes that allow them to escape the immune system. They may stop presenting the cell surface proteins that allow immune cells to detect them, for example, or they might produce substances that hinder the function of the immune system.
The situation becomes even more complex if immune cells infiltrate the tumour. In some cases, this can help the body minimise the growth of the tumour, but in others, the cancerous cells can exploit immune processes to promote their growth and spread.
In this study, the researchers wanted to better understand whether and how cancer’s ability to evade the immune system affects its genetics.
Immune evasion affects driver genes
The scientists used samples from The Cancer Genome Atlas program, analysing almost 10,000 primary tumours across 31 different cancer subtypes. Based on the presence or absence of a specific mutation in a known ‘escape gene’, they determined that 2,089 of the samples were from escaped tumours while 7,087 were from non-escaped tumours.
Further analysis revealed that the average number of mutations was more than four times higher in the cells from the escaped tumours than in those from the non-escaped tumours. Furthermore, the types of mutation were different. The escaped tumours had more missense and truncating mutations, which, respectively, change the structure and length of the resulting protein.
Keen to explore these mutations further, the researchers calculated the ratio of nonsynonymous to synonymous nucleotide substitutions, known as dN/dS. Nucleotides are the basic building blocks of DNA, and there are four different types. If a nucleotide replacement changes the corresponding amino acid in the protein, scientists refer to the substitution as nonsynonymous. When dN/dS is greater than one, this indicates positive selection, meaning that the change gives the cancer a survival benefit. The genes in which these mutations occur are known as driver genes.
The team identified 85 driver genes across all of the samples, including 43 that had not previously been reported. Interestingly, the dN/dS of driver genes in escaped tumours was significantly lower than that in non-escaped tumours. This finding suggests that without the pressure of the immune system, cancerous cell populations are not forced to change their phenotype to try to survive. Instead, they can build up genetic variation that does not alter their phenotype, which may be beneficial to their survival, growth and adaptation to future changes in their environment.
Using escape status to predict outlook
In the next stage of the study, the researchers focused on known cancer-causing genes, looking at segments of DNA – called hotspots – that have been shown to be particularly prone to genetic alteration. They were surprised to find that some of the mutations appearing in these hotspots were only present in the non-escaped tumour cells, which suggests that the immune system plays a significant part in promoting them.
Looking more closely at the patterns of mutations – known as mutational signatures – revealed that some of these were associated with external environmental exposure. The signatures linked with smoking and exposure to UV light were more common in the samples from escaped tumours, indicating that these carcinogens increase the likelihood of cancer evading the immune system.
Overall, the study showed that patients with tumours that had escaped the immune system had a lower rate of survival. A comparison between the groups showed that the difference in survival was only present in cases where the non-escaped tumours were subject to an inflammatory immune response, which occurs when the immune system responds to harmful stimuli. This suggests that the inflammatory response is key to fighting off the cancer and maximising patients’ overall survival.
Armed with the necessary genetic information, clinicians could therefore determine which patients are at risk of more aggressive tumour development. They could then plan their treatment accordingly. This would likely result in better outcomes for people with fast-growing tumours and also spare people with less aggressive tumours from excessively intensive treatment.
“Labs around the world can use our findings”
First author Lucie Gourmet, a PhD student in the Centre for Computational Medicine at University College London, said:
“It has been fascinating to investigate the interplay between genomic instability and the immune system, as cancer evolution depends on both.
“I think the most interesting finding of our study is the fact that the selective pressure of the immune system could explain mutational hotspots in non-escaped patients. Other studies indicate that these hotspot mutations involve a trade-off between the promotion of cancer and the increased chance of generating an immune response.”
Senior author Dr Luis Zapata Ortiz, Group Leader of the Evolutionary Immunogenomics Group at The Institute of Cancer Research (ICR), said:
“This study gave us the opportunity to build on previous work on immune selection and to test our theory that by inducing immune evasion, the immune system influences the distribution of mutations in driver genes. Labs around the world can use our findings to design experiments that will further our understanding of immune evasion.
“We were particularly excited to find that hotspot mutations were more prevalent in non-escaped tumours. This was very surprising, and its possible explanation opens up a new avenue of research. We have shown that, clinically, the status of immune evasion can be used to determine the aggressiveness of a tumour. Next, we plan to work on developing a method to quantify immune evasion using genetic signatures.”