California [US], Liver inflammation, a typical side effect of fatal disease elsewhere in the body, has long been associated with poor cancer outcomes and, more recently, with poor response to immunotherapy, according to the Abramson Cancer Center at the University of Pennsylvania and A team of researchers at Perelman University School of Medicine has now discovered a major reason for this. In their study published in Nature Immunology, researchers found that cancer-induced liver inflammation causes liver cells to secrete serum amyloid A (SAA) protein. They secrete proteins called proteasomes, which spread throughout the body. This prevents T cells – the immune system's primary anti-cancer weapon – from infiltrating and attacking tumors elsewhere. “We want to better understand why patients resist immunotherapy to help design more effective strategies.” What causes cancer to do or react," says senior author Gregory Beatty. , MD, PhD, an associate professor of hematology-oncology and director of clinical and translational research at the Penn Pancreatic Cancer Research Center. “Our findings show that the surviving cells – with the release of SAA protein – effectively serve as an immune checkpoint regulating anti-cancer immunity, making them a promising therapeutic target. The study builds on previous research by the team, which also includes co-lead authors Meredith Stone, PhD, a research associate, and Jessie Lee, a graduate student, on liver inflammation in cancer: In a 2019 study, they showed that How it promotes pancreatic tumor metastasis to that organ In 2021, researchers at the Beat Laboratory observed that systemic inflammation, including several SAM molecules involved in liver metastasis, is linked to worse responses to immunotherapy in pancreatic cancer patients .The latest study was designed to examine in more detail how liver inflammation might block the effects of these immune-boosting therapies. , they looked at mouse models of pancreatic cancer, measuring the amount of T-cell infiltration into pancreatic tumors – a basic indicator of anti-tumor immune activity. They found that mice whose tumors had less T cell infiltration had more inflammation in their livers. These mice also showed strong signals of an inflammatory signaling pathway called the IL-6/JAK/STAT3 pathway – the same one that the team implicated in liver metastasis in their 2019 study. The researchers further showed that STAT3 activation in liver cells is associated with reduced production of immune cells called dendritic cells, which are important for normal T cell responses.When the scientists removed STAT3 from liver cells, dendritic cell production and T cell activity increased, and tumors that previously had only low T cell-infiltration developed higher cell-infiltration. Ultimately, the team found that STAT3 in liver cells Activation has its dendritic cell- and T cell-suppressing effects by inducing the production of SAA proteins that target receptors on immune cells. Removing the SAA protein had the same immune-restoring effect as removing STAT3, and mice that had pancreatic tumors surgically removed had increased survival time and likelihood of cure. To understand whether the findings from the mouse model would translate to humans, the researchers measured SAA. levels in tissue samples from patients who had pancreatic tumors surgically removed and found that survival time was significantly longer in those with lower SAA levels after surgery. “The translational findings in human patients highlight the potential clinical relevance of our discoveries in mice.,” Beatty said. “Now that we have shown how liver inflammation hinders immunotherapy, our next step is to see if the same pathway can be targeted to reverse inflammation in patients who have Already have liver metastases."