How the immune system is unaware of pancreatic cancer

Due in part to its rapid growth and tendency to remain strangely invisible to the immune system, pancreatic cancer is infamously difficult to cure.

According to a recent study, there may be a connection between the two characteristics. Researchers discovered that MYC, a key protein that causes cancer, can change roles in response to tumour stress, assisting cancer cells in hiding by suppressing an internal danger signal that would typically trigger immune responses.

Removing this protective "cloak" in animal trials did more than only reduce the growth of tumours. Only when the immune system was functioning did it cause them to collapse.

Martin Eilers and the University of Würzburg's Cancer Grand Challenges KOODAC team spearheaded the study, working with MIT and other international collaborators.

The function of an enigmatic protein

One reason MYC is well-known in the field of cancer biology is that it stimulates cell division and growth. Tumours with strong MYC activity can grow so quickly because of this.

According to Eilers, "this protein is one of the central drivers of cell division and thus of uncontrolled tumour growth in many types of tumours." However, certain MYC-driven tumours appear to evade immune identification, which is not entirely explained by that conventional theory.

Under stress, fast-growing cancer cells frequently produce aberrant molecular waste, which is precisely what the immune system might exploit as a red flag. However, a lot of pancreatic tumours continue to go unnoticed.

A switch that is triggered by stress

According to the researchers, MYC has a second mode that is particularly significant inside tumours.

MYC binds DNA and activates genes linked to growth under normal circumstances. However, the team discovered that MYC can move away from DNA and begin latching to freshly generated RNA molecules in the stressed environment of a fast growing tumour.

MYC's behaviour is drastically altered by that modification. Several MYC proteins start to form dense clusters.

multimers with condensate-like behaviour.

Within the nucleus, these clusters serve as "gathering points" that draw other cellular machinery to the same location. The exosome complex is one of the primary recruiters.

Eliminating the alarm signals on the cell

An example of a molecular cleanup crew is the exosome complex. It is drawn into MYC clusters in this study and becomes particularly crucial for degrading RNA-DNA hybrids, which are defective consequences of gene activation.

These hybrids are important because they can activate immunological sensing pathways within the cell by acting as distress signals. MYC successfully muffles the alarm system before it can properly activate by coordinating the quick elimination of these hybrids.

The tumour doesn't simply evade detection. It actively eliminates any material that would raise suspicions about immunological defences.

A specific focus for treatment

The fact that MYC's "growth" and "immune-hiding" functions seem to be mechanistically distinct is among the most helpful details here. The study associates immune evasion with a particular MYC RNA-binding region that is not necessary for MYC's traditional function in promoting proliferation.

This is significant since it indicates a more specific therapeutic target. Because MYC is also essential for healthy cells, previous attempts to block MYC in general have failed. Theoretically, a more limited action could lessen collateral damage.

When the cloak was taken off

The researchers changed MYC so that it could no longer bind RNA efficiently in order to determine whether MYC's RNA-binding function is actually essential to immune evasion.

Without that capability, MYC was unable to inhibit the internal danger signals or recruit the exosome complex in the same manner. In animal models, the outcomes were dramatic and immunity-dependent.

According to Eilers, "tumours with a defective MYC protein collapsed during the same period and shrank by 94 percent, but only if the animals' immune systems were intact, whereas pancreatic tumours with normal MYC increased in size 24-fold within 28 days."

Put differently, the tumours did not just collapse as a result of MYC's diminished ability to promote growth. Because the immune system could now "see" and attack what had been concealed, they collapsed.

A more practical course of treatment

The main suggestion made by the researchers is not to "turn off MYC entirely." Rather, they propose a future approach in which medications solely target MYC's RNA-binding capacity, lifting the immune masquerade without running the risk of shutting down MYC across the body.

Future medications could specifically block MYC's capacity to bind RNA rather than totally inhibiting it. This would lift the tumor's veil of invisibility while possibly maintaining its growth-promoting role, according to Eilers.

Because it presents treatment as exposure rather than blunt force—removing the tumor's shield and letting the immune system do more of the work—that strategy is attractive.

What is not yet known

It will take time to translate this science into the actual world because it is still in the lab stage. The group identifies unanswered questions, such as how MYC's RNA-binding activity modifies the tumor's local immunological milieu and how these immune-activating RNA-DNA hybrids (or related signals) leave the nucleus to initiate more extensive immune pathways.

The director of Cancer Grand Challenges, Dr. David Scott, highlighted the broader importance of identifying immune-hiding mechanisms: "International teams like KOODAC that are pushing the boundaries of what we know about cancer are supported by Cancer Grand Challenges."

"This kind of research demonstrates how understanding the strategies tumours employ to evade the immune system can open up new possibilities, not only for adult cancers but also for childhood cancers that the KOODAC team is focused on."

"It's an encouraging example of how diverse expertise and international collaboration can help tackle some of the most difficult challenges in cancer research."

The headline concept is straightforward if subsequent research validates similar results in additional contexts. It's possible that pancreatic cancer actively turns off the alarm rather than being "immune invisible" by nature. Additionally, that alarm switch might be a good location to step in.