The study, published on 23 November 2022 in Cancer Cell, recommends IL1B macrophages as a promising therapeutic target to treat renal cell carcinoma given that this cell type has already been targeted using existing drugs that prevent lung cancer. The next step, which is already being explored, will be clinical trials to prove that targeting IL1B can be used to effectively prevent renal cell carcinoma from forming or progressing.
Renal cell carcinoma (RCC) is the seventh most common cancer in the UK, with three quarters of cases and the majority of deaths caused by clear cell renal cell carcinoma (ccRCC). The disease has a 50 per cent mortality rate, partially because three in five patients show no symptoms until the cancer is at a late stage1.
Many RCC tumours form when both copies of the VHL gene are switched off. A subset of patients have inherited kidney cancer, including Von Hippel-Lindau (VHL) disease2, which is a genetic condition where one copy of the VHL gene is switched off from birth. The second copy of VHL is usually switched off as a result of a common genetic event that often occurs in early life, leading to the formation of innumerable tumours.
In this new study, researchers at the Wellcome Sanger Institute and University of Cambridge studied over 270,000 single cells and 100 micro-dissections from 12 patients with kidney tumours. Samples were taken from different parts of the tumour as well as normal kidney tissue. These samples were analysed using single-cell RNA sequencing and spatial transcriptomics to map the exact location of specific cells within tissues.
This analysis highlighted a particular type of immune cell, a macrophage expressing the gene IL1B, as abundant at the fringes of tumours.
Dr Ruoyan Li, first author of the study from the Wellcome Sanger Institute, said: “Using both single-cell sequencing and spatial transcriptomics allowed us to discover not only what cell types were present in these renal cell carcinoma tumours, but how the cell types were organised in space. This approach meant we could pinpoint macrophages expressing the IL1B gene at the leading edges of tumours, acting almost like a vanguard for tumour growth.”
The findings will be of particular interest to those with VHL disease, who are highly likely to suffer numerous and persistent tumours. While kidney tumours can be monitored and surgically removed before the cancer can spread to other parts of the body, new ones will form and there is a limit to how many times patients can have surgery before losing kidney function.
John Hepworth, 62 years old, is a VHL patient with RCC. He was diagnosed in 2013 at the age of 53 and has since become one of the Trustees of the VHL UK/Ireland charity.
“We’ve known for decades that there was something going on in our family history, that there was something wrong. Out of the last five generations directly linked to me, four of my family members have died in their forties, and the fifth died at 56. I made it to 53 until the disease presented itself, which is fairly late compared to some people. Since being diagnosed my sister and uncle have had genetic testing. While my wife and I don’t have children, my sister and my uncle do, and thankfully they were both negative. I take a lot of comfort knowing that after all these decades, it stops with me.
“When I was diagnosed, it felt like I was the only one on the planet with this disease. However, around this time the VHL UK/Ireland charity was just starting up again, so I got in touch and it’s gone from there. It can be an incredibly lonely disease at times, it being so rare, and you always know you have surgery coming and that it is only a matter a time. That’s why it’s important to try and raise awareness, to make sure that people know there is a community here for them, and support if they need it.
“At the VHL UK/Ireland charity we also push for new treatments to be approved. As a community, most of us are desperate for some sort of treatment that can at least improve the situation, which includes constant scans and surgeries. While there are possibilities in the pipeline, there is nothing other there for us yet. Research is crucial if we are to find something to help, and it’s great that there is so much research, such as this, going on to try and find other options.”
Joshua Mann, MPH, Director of Health, VHL Alliance, said: “As a result of research, the outlook for those living with VHL disease has improved greatly in recent years. Even before the VHL gene was identified, the standard of care has always been a lifetime of surveillance with frequent, painful, and expensive surgeries to remove tumours interspersed within the body. We are approaching a new era of managing VHL disease, with a major paradigm shift that could eventually even do away with these surgeries. A way to treat VHL-related tumours without surgical intervention would be a huge boost for those with the condition. The VHL Alliance is actively exploring opportunities to bolster and support these important research efforts.”
The researchers are already planning clinical trials to test whether targeting IL1B macrophages is an effective treatment for RCC. The fact that existing drugs targeting this pathway are proven to be effective in preventing some lung cancers offers hope that these trials may deliver promising results.
Dr Thomas Mitchell, a senior author of the study from the Wellcome Sanger Institute and the University of Cambridge, said: “I’m optimistic that targeting IL1B macrophages may provide us with a way to treat renal cell carcinomas without resorting to surgery. This will be particularly important for patients with VHL disease because we should be able to prevent tumours forming in the first place by focusing on their genetic roots, rather than waiting for them to grow and removing them. As is the case for all cancers, the earlier we can intervene the better.”
Image: Single cells in kidney tissue. Majority are cancer cells and have the small yellow dots around them. Credit: Omer Bayraktar & Kenny Roberts/Wellcome Sanger Institute.
