From ceu.ox.ac.uk
Higher levels of proteins involved in activating and coordinating the immune system were associated with a lower risk of developing prostate cancer, in a new study led by researchers at Oxford Population Health.
The findings suggest that the body’s ability to recognise and respond to abnormal cells may play an important role in the early development of prostate cancer, and could point to new approaches for preventing the disease.
The study, published in Nature Communications, is the largest and most comprehensive prospective and genetic analysis of circulating immune and inflammation-related proteins in relation to prostate cancer risk. Prostate cancer is the most common cancer in UK men, yet its known risk factors (age, ethnicity, family history and genetics) are non-modifiable, and there are no established strategies for prevention.
The researchers analysed blood samples from thousands of men to investigate whether proteins involved in inflammation and immune function were associated with subsequent prostate cancer risk. They examined 368 immune- and inflammation-related proteins using the European Prospective Investigation into Cancer and Nutrition (EPIC), comparing 1,434 men who developed prostate cancer, on average more than a decade later, with 1,434 similar men who did not.
The researchers also analysed data from 21,481 UK Biobank male participants including 1,147 prostate cancer cases, and used genetic approaches to investigate whether the relationships between proteins and prostate cancer were likely to be causal.
One of the strongest findings involved interleukin-15 (IL-15), a protein that helps stimulate and maintain cancer-fighting T cells and natural killer (NK) cells. Across the combined analyses, higher levels of IL-15 were associated with a 14% lower risk of prostate cancer diagnosed more than seven years later. In the EPIC cohort, where information on tumour characteristics was available, higher IL-15 was also associated with a 26% lower risk of advanced prostate cancer.
Several other immune-related proteins showed similar associations. Higher levels of FLT3LG, BCL2L11, PGF, CKAP4 and TNFRSF11A were each associated with a lower risk of prostate cancer more than seven years after blood collection.
Dr Mahboubeh Parsaeian, lead author of the study and Senior Medical Statistician at Oxford Population Health, said:
Prostate cancer had been considered immunologically "cold" ‒ unlikely to trigger a strong immune response or prevent the body from using its own defence system to kill the cancer cells ‒ but we normally study the immune system after the tumour is already there. Our findings suggest that the immune system does, in fact, play a role in the early development or suppression of prostate cancer.
The associations we found cannot give us a complete understanding of the underlying biology ‒ how these proteins act, and interact, during cancer development ‒ but they do suggest that existing drugs which manipulate these pathways could offer a way of intervening while men are still healthy, rather than treating the disease after diagnosis.
The study also identified a separate potential route involving PARP1, a DNA-repair protein. Using genetic data, researchers found that men genetically predisposed to higher PARP1 levels had an increased risk of prostate cancer, a finding which has been replicated in an independent, multi-ethnic cohort. PARP inhibitors such as olaparib are used to treat some prostate cancers, particularly tumours with defects in DNA repair pathways such as BRCA1 or BRCA2, but they are not currently used for cancer prevention.
Professor Karl Smith-Byrne, Senior Molecular Epidemiologist at Oxford Population Health, and a senior author of the paper, said:
What is striking in our study is that the strongest immune signals were present more than seven years before diagnosis, pointing to a much earlier period when the immune system may be helping to keep abnormal cells under control.
IL-15 is particularly interesting because it supports natural killer cells and killer T cells, which are precisely the cells we would expect to participate in this kind of surveillance for abnormal cells. The PARP1 finding raises a striking possibility: that a pathway already targeted after prostate cancer develops might also influence whether the disease develops in the first place.
The researchers will test how these proteins interact and whether influencing them alters risk, with the longer-term aim of translating these findings into ways to prevent the cancer, rather than treating it after diagnosis, through the Prostate Cancer Aetiology and Prevention (PCAP) programme, funded by Cancer Research UK.
Dr Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, said:
This research suggests that the immune system may play an important role in preventing prostate cancer long before it becomes detectable. The link between our immune system and lower cancer risk offers new insights into how the body controls emerging cancer cells, and further research could help find ways to harness the immune system to prevent prostate cancer in the first place.
Professor Ruth Travis, one of the PCAP programme leads said:
These richly characterised population studies are transforming our understanding of cancer. For the first time, they allow us to examine the biology of the disease years before it is diagnosed.
By analysing thousands of proteins, we are uncovering new clues about the mechanisms that influence who develops prostate cancer and who does not. These insights could help us move towards more effective prevention strategies, and identify the critical windows during which intervention may have the greatest impact.
Case study
Dafydd Charles, committee member of the Oxfordshire Prostate Cancer Support Group and PCAP patient representative, said:
In late 2017, I had recently turned 60 and was feeling well when I visited my GP to discuss prostate health. I had no symptoms and thought it would be a routine consultation. I was shocked to discover that I had aggressive prostate cancer which had already spread to nine lymph nodes throughout my abdomen.
I subsequently underwent three years of intensive treatment, including surgery, hormone therapy, chemotherapy and pelvic radiotherapy. Although the treatment successfully eradicated the disease, it left me with significant side effects.
During the final stages of my treatment, I was invited to take part in research investigating my genetic risk of prostate cancer. I was particularly keen to participate because I have two grown-up sons and wanted to understand whether they might also be at increased risk. The tests suggested that inherited genetic changes could have contributed to my diagnosis
That experience inspired me to support research into why some men develop prostate cancer and whether their risk could be reduced before the disease takes hold.
This latest research is particularly encouraging because it investigates the role of the immune system years before prostate cancer is diagnosed. The possibility that such discoveries could eventually lead to ways of preventing the disease, rather than just treating it after diagnosis, is hugely inspiring for patients, their families and future generations.
https://www.ceu.ox.ac.uk/news/stronger-immune-system-may-help-protect-against-prostate-cancer
