Image: Low levels of NBR1 in hepatic stellate cells enhance interferon signaling in human hepatocellular carcinoma (photo courtesy of Moscat and Diaz-Meco laboratories)
Until recently, patients diagnosed with hepatocellular carcinoma had limited treatment options, as existing therapies extended life by only a few months. Immunotherapy has emerged as a new alternative for these patients, which could prolong their life by up to two years. However, not all patients respond to immunotherapy and only a small fraction achieve long-term remission, making it difficult for doctors to predict who might benefit. Now, a preclinical study suggests that it will soon be possible to identify which patients with hepatocellular carcinoma would respond favorably to immunotherapy.
In this study, researchers at Weill Cornell Medicine (New York, NY, USA) sought to discover biomarkers and therapeutic targets by investigating the liver’s healing mechanisms and how they can lead to cancer. The study provides new insights into two proteins, p62 and NBR1, and their contrasting roles in modulating the interferon response in hepatic stellate cells, which are vital for the liver’s immune response against tumors. Previous research indicated that levels of the tumor suppressor protein p62 are permanently reduced in patients who develop hepatocellular carcinoma. The new findings revealed that p62 normally promotes an immune response by activating a protein known as STING, which displaces the immunosuppressive NBR1, thereby initiating an immune response that targets tumor cells. In contrast, NBR1 facilitates STING degradation and inhibits the immune response. Deletion of NBR1 from hepatic stellate cells in mice with hepatocellular carcinoma restored the immune response and reduced tumor size, even when p62 levels remained low.
Thus, the findings of the study, published in Molecular Cellindicated that elevated levels of NBR1 in these specialized cells could identify patients who are unlikely to respond to immunotherapy. Furthermore, strategies aimed at reducing NBR1 levels were shown to shrink tumors in animal models, indicating a potential new treatment approach for patients who do not respond to immunotherapy. The research team is now exploring the development of a therapy that would degrade NBR1 in patients, preventing it from interacting with STING. Its objective is to reactivate the immune system and improve the effectiveness of immunotherapy. Drugs that activate STING are also being developed and may offer another strategy to stimulate the immune response in patients with hepatocellular carcinoma. Additionally, the team plans to investigate whether reducing NBR1 could help prevent metastasis of various types of cancer or prevent tumors from becoming resistant to treatment. They intend to continue their exploration of the pathways that regulate the liver’s immune response.
“If we do not fully understand the molecular mechanisms that regulate these processes, immunotherapy will not progress and we will not be able to understand why it works in some patients and not others,” said co-principal investigator Dr. María Díaz-Meco, professor of Oncology at Homer T. Hirst Pathology and member of the Meyer Cancer Center at Weill Cornell Medicine.
