Decoded: How cancer cells protect themselves from the immune system

Could this mark a shift in how we think about cancer therapy? At least in the laboratory, evidence suggests it may be. An international research team has succeeded in deciphering a key mechanism that controls the growth of pancreatic cancers. The scientists identified a potential central mechanism by which cancer cells protect themselves from attack by the body's own immune system. Blocking this mechanism resulted in a dramatic reduction in tumours in laboratory animals.

A look at the central driver of cell division

The results of the study have now been published in Cell. The research was primarily carried out by Leonie Uhl, Amel Aziba and Sinah Löbbert, along with other collaborators from the University of Würzburg (JMU), Massachusetts Institute of Technology (USA) and Würzburg University Hospital.

The study was led by Martin Eilers, Chair of Biochemistry and Molecular Biology at JMU, as part of the Cancer Grand Challenges KOODAC* team. The project was partly funded by Cancer Research UK, the Children Cancer Free Foundation (Kika) and the French National Cancer Institute (INCa) as part of the Cancer Grand Challenges initiative. Additional funding came from an Advanced Grant from the European Research Council awarded to Martin Eilers.

In their study, the researchers focused on a specific protein that has long been known in cancer research: the oncoprotein MYC. “In many types of tumours, this protein is one of the central drivers of cell division and thus of uncontrolled tumour growth,” explains Martin Eilers. However, one crucial question remained unanswered: How do tumours with high MYC activity manage to evade the body's immune defences? Although MYC-driven tumours grow very rapidly, they often remain invisible to the immune system.

A second face of the cancer gene

The answer to this question is provided by the recently published study. The key discovery made by the international research team is that MYC has a dual function. In addition to its known role of binding to DNA and activating growth-promoting genes, it can change its function when the cell is under stress. Under the chaotic conditions that prevail in rapidly growing tumours, MYC takes on a new function: instead of binding to DNA, it binds to newly formed RNA molecules.

This binding to RNA has far-reaching consequences: several MYC proteins form dense clusters, known as multimers, which function like molecular condensates. These “droplets” act as collection points, specifically attracting other proteins — in particular the exosome complex —and concentrating them in one place.

The exosome complex then breaks down cellular waste products in a very targeted manner – primarily so-called RNA-DNA hybrids. These are defective products of gene activity and normally act like a loud alarm signal inside the cell, signalling to the immune system that something is wrong.

How MYC tricks the immune system

This is precisely where MYC's camouflage function comes into play. By organising the degradation of RNA-DNA hybrids with the help of exosome complexes, it eliminates the alarm signals before they can activate the immune defence. As a result, the downstream signalling chain does not even get started. The tumour remains invisible to the immune cells.

The researchers were able to demonstrate that an RNA-binding region within the MYC protein is responsible for this camouflage. Crucially, this region is not required for MYC's growth-promoting function, i.e. its ability to bind to DNA. The two functions – driving growth and deceiving the immune system – are mechanistically separate.

A targeted strike against the tumour in an animal model

The next step was obvious: MYC proteins with a genetically modified RNA-binding region should no longer be able to call on the exosome for help and block the alarm pathway. Indeed, the consequences of this discovery were dramatic in the corresponding experiments in animal models: “While pancreatic tumours with normal MYC increased in size 24-fold within 28 days, tumours with a defective MYC protein collapsed during the same period and shrank by 94 per cent – but only if the animals' immune systems were intact,” says Martin Eilers, describing the key finding of the study.

Outlook and therapeutic potential

These results open up promising new avenues for cancer therapy. Previous attempts to completely block MYC have proven difficult because the protein is also important for healthy cells. The newly discovered mechanism now offers a much more specific target.

“Instead of completely switching off MYC, future drugs could specifically inhibit only its ability to bind RNA. This would potentially leave its growth-promoting function untouched, but lift the tumour's cloak of invisibility,” explains Eilers. The tumour would thus become visible and vulnerable to the immune system again.

However, the scientist warns that there is still a long way to go before a corresponding therapy is ready for the market. The next step is to clarify exactly how the immune-stimulating RNA-DNA hybrids are transported out of the cell nucleus and how MYC's RNA binding influences the immediate environment of the tumour.

Commenting on the study, Dr David Scott, Director of Cancer Grand Challenges, said: “Cancer Grand Challenges exists to support international teams like KOODAC that are pushing the boundaries of what we know about cancer. Research like this shows how uncovering the mechanisms tumours use to hide from the immune system can open up new possibilities, not only for adult cancers but also for childhood cancers that are the focus of the KOODAC team. It’s an encouraging example of how international collaboration and diverse expertise can help tackle some of the toughest challenges in cancer research.“

Cancer Grand Challenges

Co-founded in 2020 by two of the largest supporters of cancer research in the world: Cancer Research UK and the National Cancer Institute, Cancer Grand Challenges supports a global community of diverse, world-class research teams to come together, think differently and take on some of cancer’s toughest challenges. These are the obstacles that continue to impede progress and no one scientist, institution or country will be able to solve them alone. With awards of up to £20m, Cancer Grand Challenges teams are empowered to rise above the traditional boundaries of geography and discipline to make the progress against cancer we urgently need.