Central to a healthy immune system is a family of proteins known as toll-like receptors, or TLRs, that acts like a pack of watchdogs trained to recognize and warn of dangerous microbes. “Their primary job is to bind by-products of infectious agents, such as bacteria and viruses and fungi, and mount an immune response,” says George Miller, MD, associate professor of surgery and cell biology at Pelisyonkis Langone. Other researchers have found that these receptors, discovered in the 1990s, can also bind the by-products of inflammation and cell death—the body’s own “inflammatory junk”—and turn on a potent immune response that, in select circumstances, can target cancerous cells for destruction.
In a new twist reported in The Journal of Experimental Medicine, Dr. Miller and colleagues recently found that at least one TLR protein can be co-opted by an aggressive pancreatic cancer. In susceptible mice, the researchers discovered that a TLR protein known as TLR9 can actually promote the equivalent of human pancreatic ductal adenocarcinoma. Deleting the receptor’s gene or blocking its function, conversely, protected the mice against tumor progression—an unexpected finding that points to a potential therapeutic target for a devastating disease.
More than 95 percent of patients succumb within five years of being diagnosed with pancreatic ductal adenocarcinoma, making it the fourth deadliest kind of cancer in the United States. Chronic inflammation of the pancreas can increase the risk of this cancer by 15-fold, and multiple studies have linked inflammation to the cancer’s progression. The mechanism behind the initial tumor formation, however, has remained unclear.
The new study’s key experiments used mice with a pancreatic cancer–linked genetic mutation. When the researchers activated TLR9 by adding the right mix of molecular bait for the protein to recognize and latch onto, tumor formation ensued, and the cancer accelerated. In these mice, additional experiments showed that the receptor gets turned on in a subset of pancreatic cells that mature and then pump out chemicals that promote tumor cell proliferation and keep the immune system suppressed within the tumor.
By genetically blocking or deleting the gene for TLR9, the researchers were able to protect the mice from tumor formation and improve their odds of survival. “The clinical implication is to potentially use this strategy in patients who are at high risk for pancreas cancer, to block TLR9,” Dr. Miller says. Several research groups are already investigating small molecules that may block the receptor and work as anticancer agents.
Intriguingly, the research findings also implicate the microbiome, or the entire collection of microbes that naturally inhabit the gut, in pancreatic cancer. The study suggests that certain gut-dwelling bacteria can move into the pancreas. Once there, bacterial DNA sequences bind to TLR9, which then signals pancreatic cells to begin releasing the tumor-aiding chemicals.
This pancreatic cancer–boosting mechanism, it seems, may be hijacking a microbial system originally intended to ensure that the body’s immune system doesn’t attack naturally occurring microorganisms. “It’s a circumstantial thing. You’re not going to get pancreatic cancer just from the microbes,” Dr. Miller says. In someone with the right cancer-promoting genetic mutation, however, the microbes may help tip the scales toward tumor formation.
In other studies, Dr. Miller’s group has identified a shift in the microbial profile of patients with pancreatic ductal adenocarcinoma, when compared to healthy counterparts. More-detailed information about which microbes are setting those patients apart could be applied to follow-up studies in mice to zero in on the molecular factors that may be turning our natural watchdogs against us, causing them to dampen the immune system and abet the deadly cancer.