Biomarker Could Predict Immunotherapy Response in Liver Cancer

Until recently, patients diagnosed with hepatocellular carcinoma had limited treatment options, with existing therapies extending life by only a few months. Immunotherapy has emerged as a new alternative for these patients, potentially extending their lives 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 clinicians to predict who might benefit. Now, a preclinical study suggests it may soon be possible to identify which patients with hepatocellular carcinoma would respond favorably to immunotherapy.

In this study, investigators at Weill Cornell Medicine (New York, NY, USA) sought to uncover biomarkers and therapeutic targets by investigating the liver’s healing mechanisms and how they can lead to cancer. The study offers fresh insights into two proteins, p62 and NBR1, and their contrasting roles in modulating the interferon response in hepatic stellate cells, which are vital to the liver's immune response against tumors. Previous research indicated that levels of the tumor-suppressing protein p62 are permanently reduced in patients who develop hepatocellular carcinoma. The new findings revealed that p62 typically fosters an immune response by activating a protein known as STING, which displaces the immune-suppressing NBR1, thereby initiating an immune response that targets tumor cells. Conversely, NBR1 facilitates the degradation of STING and inhibits the immune response. Removing NBR1 from hepatic stellate cells in mice with hepatocellular carcinoma restored the immune response and reduced tumor size, even when p62 levels remained low.

Image: Low NBR1 levels in hepatic stellate cells enhance interferon signaling in human hepatocellular carcinoma (Photo courtesy of Moscat and Diaz-Meco labs)

Thus, the study findings, published in Molecular Cell, indicated that elevated NBR1 levels in these specialized cells could identify patients who are unlikely to respond to immunotherapy. Additionally, strategies aimed at reducing NBR1 levels were shown to diminish 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. Their objective is to reactivate the immune system and enhance the efficacy of immunotherapy. Drugs that activate STING are also being developed and may offer another strategy to boost the immune response in patients with hepatocellular carcinoma. Furthermore, the team plans to investigate whether reducing NBR1 could help prevent the metastasis of various cancer types or stop tumors from becoming resistant to treatment. They intend to continue their exploration of the pathways that regulate the liver's immune response.

“If we don’t fully comprehend the molecular mechanisms regulating these processes, immunotherapy will not progress, and we won't be able to understand why it works in some patients and not others,” said co-principal investigator Dr. Maria Diaz-Meco, the Homer T. Hirst Professor of Oncology in Pathology and a member of the Meyer Cancer Center at Weill Cornell Medicine.