New Insights into Pancreatic Cancer’s Immune Evasion
Pancreatic ductal adenocarcinoma is known as one of the most aggressive cancers, often referred to as “cold” in terms of immune response. Researchers have long understood that high levels of the MYC protein drive tumor growth, but how these rapidly growing tumors evade immune detection remained a mystery.
Recently, an international research team, led by the University of Würzburg and including collaborators from MIT and Würzburg University Hospital, identified a mechanism they describe as a molecular “invisibility switch.” Their findings, published in Cell, reveal that MYC can transition from its well-known function in DNA binding to a role that suppresses innate immune signaling.
MYC’s Dual Role Under Cellular Stress
MYC is recognized as a major driver of uncontrolled cell division, forming a complex with MAX that binds to various genetic elements across the genome, altering gene expression in tumors. However, this new research shows that MYC doesn’t always remain tethered to DNA.
According to the study, under conditions where transcription is disrupted and intronic RNA starts to accumulate, MYC shifts from DNA to nascent RNA. In this RNA-focused state, MYC clusters around double-stranded RNA and structures known as R-loops, containing RNA-DNA hybrids.
The study highlights that MYC consists of four RNA-binding regions, labeled RBRI through RBRIV, with RBRIII being particularly crucial. This region facilitates MYC multimerization and helps recruit the nuclear exosome, an RNA-degrading complex, to areas where abnormal RNA structures are present. This RNA-binding function is notably separate from MYC’s well-established role in activating transcription.
Preventing Immune Alarms from Activating
Normally, RNA-DNA hybrids formed through R-loops can initiate immune pathways. These hybrids are detected by the pattern recognition receptor TLR3, which subsequently triggers TBK1, leading to downstream immune signaling activation.
The research indicates that MYC, through its RBRIII domain, suppresses this alarm system. By recruiting the nuclear exosome to degrade RNA related to R-loops, MYC limits the accumulation of RNA-DNA hybrids, preventing the activation of TLR3 and TBK1.
The study found that pancreatic tumor cells with a mutant MYC that cannot bind RNA through RBRIII were unable to suppress TBK1 autophosphorylation, which indicates TBK1 activation. While both the wild-type and mutant MYC promoted cell proliferation in culture, only the wild-type MYC effectively silenced gene sets associated with innate immune signaling pathways like NF-κB and interferon.
This distinction became even clearer in live models. In a mouse model using pancreatic KPC cells, tumors with normal MYC expanded significantly over 28 days, while tumors with the RBRIII mutant shrank by 94 percent during the same time frame, but only in mice with active immune systems.
Importance of Immune Recognition for Tumor Regression
These live experiments highlighted a vital point: MYC’s RNA-binding function isn’t necessary for cell proliferation in culture but is crucial for maintaining tumor growth when the immune system is intact.
Martin Eilers, a senior author of the study, pointed out that when the immune system successfully identifies the tumor, it can trigger tumor regression. Deleting or mutating the RBRIII domain didn’t impede MYC’s ability to bind to promoters or activate canonical MYC target genes, but it did disrupt MYC’s function in preventing the build-up of R-loop-derived RNA-DNA hybrids on TLR3.
Further evaluation showed that cells with the RBRIII mutant accumulated greater levels of R-loops within MYC-bound genes. This led to the activation of TBK1 and immune signaling. The authors suggest that MYC’s RNA binding acts as a stress response that shields tumors from immune attacks by preventing the triggering of innate defenses.
This discovery clarifies how MYC’s function in promoting growth is separate from its role in evading the immune system. Instead of attempting to fully inhibit MYC—something that has proven challenging due to its essential functions in normal cells—targeting its RNA-binding ability could make tumors more vulnerable to immune responses while preserving its transcriptional activities.
