Liver protein directs T cells away from tumors

circleWhen harnessing immune cells to fight cancer, researchers have traditionally focused on T cells or natural killer cells that circulate in the blood. But a key cell type orchestrating this immune response may be hiding in unexpected organs. Over the past five years, Gregory BeattyThe University of Pennsylvania oncologist suspects there may be a problem with one organ in particular: the liver.

The liver’s workhorse hepatocytes are known for filtering toxins from the blood and metabolizing nutrients, but they also release proteins that send signals to immune cells far away. Some of these proteins form part of what’s known as the acute-phase response — a tsunami of inflammatory molecules that race through the bloodstream and stimulate an immune response within hours of infection. Despite this core function of hepatocytes, “most immunologists don’t think about the liver,” says Dr. Cliona O’FarrellyHe is a researcher at Trinity College Dublin and is separately investigating the liver’s role in immunity.

There is evidence that the liver plays a powerful role in cancer immunity. Liver metastases specific Liver-associated immune proteins It reduces the patient’s response to immunotherapy.^1,2 A new study published in 2011 found that Nature ImmunologyBeatty and his team further highlighted the importance of the liver in anti-cancer immunity by activating specific signaling pathways in hepatocytes. Decreased T cell infiltration Spread to tumors outside the liver.³ This resulted in poorer cancer outcomes.These findings highlight the possibility that the liver could be harnessed to control an effective immune system attack on tumours.

“The liver is a new immune checkpoint that we should be thinking about,” Beatty says, “and finding ways to target it therapeutically holds great promise.”

Beatty’s Team Previously investigated Although the researchers had uncovered patterns of immune molecule levels in liver cells of cancer patients, they still wondered how these liver changes correlated with changes in the tumor itself that could affect long-term outcomes.^Four For example, T cell-rich tumors typically Better Results After treatment.^Five

In the new study, the researchers compared mice with different numbers of T cells in their pancreatic tumors. They found that animals with more T cell infiltration in tumors had lower levels of the immune transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver. They also measured serum amyloid A (SAA), an acute phase protein normally produced in the liver, and found that the levels were lower in mice with more T cell infiltration. In a previous study, the researchers showed that these molecules promote liver metastasis.^Four

To further elucidate the liver’s role in this immune pathway, the team genetically reduced production of these molecules specifically in liver cells. “All of a sudden, we saw all these T cells appear in the tumor,” Beatty says. “It was amazing.” Through additional genetic experiments, the team found that SAA signals to the Toll-like receptor 2 protein on another immune cell type, instructing the T cells to infiltrate the tumor.

Inspired by these findings, Beatty wanted to know whether lowering SAA levels could boost anti-cancer responses and survival rates. Vinod BalachandranIn a study, oncologist John Myers, PhD, of the Memorial Sloan Kettering Cancer Center and his colleagues genetically reduced SAA in mice with pancreatic tumors and low T cells. Compared with mice with normal SAA, the genetically modified mice had more T cells in their tumors and survived longer after surgery to remove their tumors. When the team looked at data from 25 patients with pancreatic cancer, they found a similar pattern: Mice that survived longer after surgery had lower SAA levels than those who survived shorter periods.

“Despite the vast amount of literature written about SAA, we don’t actually know what its primary role is,” says O’Farrelly, who was not involved in the study. “It’s really interesting that this paper gives SAA a completely different role.”

Although Beatty focused on pancreatic cancer and melanoma in this study, previous work from his group has shown the importance of SAA in lung and colorectal cancer, suggesting that the protein may play a role in many types of cancer.^Four Andreas BergthalerImmunologist David Schneider of the Vienna Center for Molecular Medicine, who was not involved in the study, believes the work adds an important piece to the puzzle of liver immune function. “It’s a great example of uncovering the interplay between organs,” he said.

However, Bergshaller’s own experience has shown that proteins produced in the liver Antiviral T cell response This means that it can be difficult to pinpoint which protein is at work among the dozens of proteins involved in a particular pathway.⁶ He hopes that future studies will show that interfering with the SAA protein or other components of the STAT3 pathway will slow cancer progression.

Finding these targets is Beatty’s top priority. Additionally, he recognizes that other diseases, such as cardiovascular disease and diabetes, can also cause liver inflammation, and he wants to study how those conditions affect anti-cancer immunity.

“If we can come up with a strategy to intervene in liver inflammation, [the] “It improves outcomes for patients undergoing surgery,” he said. “This could be a breakthrough for many patients.”