femaleWhen it comes to harnessing immune cells to fight cancer, researchers have traditionally focused on T cells, or natural killer cells, that circulate through the blood. However, important cell types that coordinate these immune responses may be hidden in unexpected organelles. Over the past 5 years, Gregory BeattyAn oncologist at the University of Pennsylvania, he was particularly suspicious of one organ: the liver.
Hepatocytes, the liver’s workhorses, are known for filtering blood toxins and metabolizing nutrients, but they also release proteins that can signal to distant immune cells. Some of these proteins make up a phenomenon known as the acute phase response. That is, a tsunami of inflammatory molecules that travel through the bloodstream within hours of infection, promoting an immune response. Despite these key functions of liver cells, “most immunologists don’t think about the liver,” he said. Cliona O’FarrellyResearchers at Trinity College Dublin separately studied the liver’s role in immunity.
There is evidence that the liver plays a powerful role in cancer immunology. liver metastases and high level specific liver-related immune proteins Reduces the patient’s response to immunotherapy.1,2 In a new study published in natural immunologyBeatty and his team further highlighted the importance of the liver in anti-cancer immunity by showing the activation of specific signaling pathways in hepatocytes. Reduced T cell infiltration With a tumor outside the liver.three This ultimately worsened cancer outcomes. These findings highlight the possibility of using the liver to control the immune system’s effective attack on tumors.
“The liver is a new immune gateway that we need to think about,” Beatty said. “It’s about finding targeting methods that have a lot of therapeutic potential.”
Beatty’s Team previously investigated Although they studied patterns at the level of immune molecules in liver cells during cancer, they still wondered how these changes in the liver could parallel changes in the tumor itself, affecting long-term outcomes.4 For example, T-cell-rich tumors typically better results After treatment.5
In the new study, researchers compared mice with varying numbers of T cells in pancreatic tumors. They found that animals with high T cell infiltration in their tumors had lower levels of the immune transcription factor signal transducer and activator of transcription (STAT3) in the liver. Moreover, measurements of serum amyloid A (SAA), an acute-phase protein normally produced in the liver, showed that levels were lower in mice with high T cell infiltration. In previous studies, researchers showed that these molecules promote liver metastasis.4
To further clarify the liver’s role in this immune pathway, the team genetically reduced the production of these molecules specifically in hepatocytes. “Suddenly there were all these T cells in the tumor,” Beatty said. “It was amazing.” Through additional genetic experiments, the team determined that SAA signals the Toll-like receptor 2 protein on another type of immune cell, which directs T cells to infiltrate the tumor.
Motivated by these findings, Beatty wanted to know whether reducing SAA levels could promote anticancer response and survival. He formed a partnership. Vinod BalachandranAn oncologist at Memorial Sloan Kettering Cancer Center, he worked on genetically reducing SAA in mice with pancreatic tumors that had few T cells. Compared with mice with normal SAA, the transgenic animals had more T cells in their tumors and had longer survival after surgery to remove the tumors. The team found a similar pattern when they examined data from 25 patients with pancreatic cancer. People who survived longer after surgery had lower SAA levels than those who survived short-term.
“Despite the enormous amount of literature that has been written about SAA, we don’t really know what its main role is,” said O’Farrelly, who was not involved in the study. “It’s really fascinating that this paper gives SAA a completely different role.”
Beatty focused on pancreatic cancer and melanoma for this study, but his group’s previous work showed the importance of SAA in lung and colon cancer, suggesting that this protein may play a role in many different types of cancer. do.4 Andreas BergthalerThe immunologist at the Vienna Center for Molecular Medicine, who was not involved in the study, believes the study adds an important piece to the puzzle of the liver’s immune capacity. “This is a great example of depicting long-term crosstalk,” he said.
But Bergthaler knows from his own experience that the proteins produced by the liver are linked to: Antiviral T cell response The problem is that among the dozens of proteins involved in a given pathway, it can be difficult to pinpoint the protein that works.6 He hopes future research will show that interfering with the SAA protein or other components of the STAT3 pathway slows cancer progression.
Finding those goals is a priority for Beatty. Moreover, he recognizes that other diseases, such as cardiovascular disease and diabetes, can also cause liver inflammation, so he hopes to study how these diseases may affect anti-cancer immunity.
“If we can come up with a strategy to intervene in liver inflammation, we can make a difference. [the] “Patients who undergo surgery will have good results,” he said. “This could be a game changer for many patients.”
References
1.Tumeh PC et al. Liver metastasis and treatment results using anti-PD-1 monoclonal antibody in melanoma and NSCLC patients. cancer immune resolution. 2017;5(5):417-424.
2. Laino AS, et al. Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition. J ImmunOther Cancer. 2020;8(1):e000842.
3. Stone ML, et al. Hepatocytes mediate immune evasion of cancer through release of serum amyloid A protein. Nat Immunol. 2024;25(5):755-763.
4. Jaewook Lee et al. Hepatocytes direct the formation of the metastatic niche in the liver.. nature. 2019;567(7747):249-252.
5. Bruni D, et al. Immune structure and immune score in cancer prognosis and treatment efficacy. Nat Lev Arm. 2020;20(11):662-680.
6. Lercher A, et al. Type I interferon signaling inhibits T cell function by disrupting the hepatic urea cycle and altering systemic metabolism.. immune. 2019;51(6):1074-1087.e9.
