p62 and NBR1 Levels Predict Immunotherapy Response in Liver Cancer
Key Insights
Researchers have identified that high levels of NBR1 (search) in hepatic stellate cells indicate a poor response to immunotherapy (search) in hepatocellular carcinoma (search) (HCC (search)).
Conversely, elevated p62 (search) levels in hepatic stellate cells may offer protective effects against cancer by enhancing the immune response.
Lowering NBR1 (search) in animal models shrank tumors, suggesting it as a therapeutic target to enhance immunotherapy (search) response in HCC (search).
Researchers at Weill Cornell Medicine have discovered that the levels of two proteins, p62 (search) and NBR1 (search), can predict a patient's response to immunotherapy (search) for hepatocellular carcinoma (search) (HCC (search)). The study, published in Molecular Cell, reveals opposing functions of p62 and NBR1 in regulating interferon response within hepatic stellate cells, which are crucial for the liver's immune response against tumors.
The research indicates that high NBR1 (search) levels in hepatic stellate cells correlate with a poor immunotherapy (search) response. In contrast, elevated p62 (search) levels may protect against cancer by boosting the immune response. Animal model studies showed that reducing NBR1 led to tumor shrinkage, marking it as a potential therapeutic target to improve immunotherapy outcomes.
"P62 (search) and NBR1 (search) are yin and yang," said Jorge Moscat, MD, PhD, a professor of oncology in pathology at Weill Cornell Medicine. He added, "If p62 is high in hepatic stellate cells, a patient is protected from cancer, but if it is low, the immune system is knocked down. If NBR1 is high, the immune system is impaired, but if NBR1 is low, the immune response increases."
HCC (search) has a grim prognosis, with limited treatment options that typically extend life by only a few months. While immunotherapy (search) can extend survival by up to two years, only 15–30% of patients respond. A significant challenge is the lack of biomarkers to predict which patients will benefit from immunotherapy.
Maria Diaz-Meco, MD, PhD, also a professor of oncology in pathology at Weill Cornell Medicine, emphasized the need for predictive biomarkers and the therapeutic potential of their research: "We need biomarkers to identify which patients will respond and who will achieve long-term survival. The liver is an organ that is tremendously immune suppressed. Reactivating the immune system is a very attractive approach that is now bearing fruit."
The team focused on the tumor-suppressing protein p62 (search), which is often depressed in HCC (search) patients. Their investigation revealed that p62 promotes immune response by activating the STING protein (search), which then displaces NBR1 (search), triggering an immune response against the tumor. NBR1, conversely, breaks down STING and blocks immune response. Deleting NBR1 from hepatic stellate cells in mouse models "rescued" the immune response, even with low p62 levels.
Therapeutic Implications
Based on these findings, Moscat, Diaz-Meco, and their team aim to develop a therapeutic strategy to degrade NBR1 (search) and prevent its interaction with STING. This approach could reactivate the immune response in HCC (search) patients and enhance the effectiveness of immunotherapies. They also plan to explore whether NBR1 knockdown benefits immunotherapy (search) in other cancers.
"If we don’t fully comprehend the molecular mechanisms regulating these processes, immunotherapy (search) will not progress, and we won’t be able to understand why it works in some patients and not others," Diaz-Meco concluded.