Predictive Biomarker May Help Identify Patients Who Could Benefit from Immunotherapy in Liver Cancer Cases: Study - Video

It may soon be possible to determine which patients with a type of liver cancer called hepatocellular carcinoma would benefit from immunotherapy, according to a preclinical study by Weill Cornell Medicine investigators.

The study, published in Molecular Cell, provides new insights into a pair of proteins, called p62 and NBR1, and their opposing functions in regulating the interferon response in hepatic stellate cells, a critical immune component in the liver’s fight against tumors. The study demonstrates that high levels of the immune-suppressing NBR1 in these specialized cells may identify patients who are unlikely to respond to immunotherapies. It also shows that NBR1-lowering strategies help shrink tumors in animal models, suggesting a potential new therapeutic approach for the subset of patients who do not respond to immunotherapy.

“P62 and NBR1 are yin and yang,” said the study’s co-principal investigator Dr. Jorge Moscat, the Homer T. Hirst III Professor of Oncology in Pathology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “In contrast to NBR1, 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.”

Until recently, patients with hepatocellular carcinoma had few treatment options and those that were available extended life by only a few months. Immunotherapy has offered a new alternative for these patients and may extend their lives for up to two years.

However, not all patients respond to immunotherapy, and only a small percentage achieve long-term remission. Clinicians cannot currently predict which patients would benefit. “We need biomarkers to identify which patients will respond and who will achieve long-term survival,” she said.

The investigators aimed to identify biomarkers and potential therapeutic targets by studying what goes wrong in the liver’s healing mechanisms that leads to cancer. Prior research has found that levels of the tumor-suppressing protein p62 are irreversibly depressed in patients who develop hepatocellular carcinoma. The new study shows that, usually, p62 helps promote an immune response by activating a protein called STING, which pushes NBR1 out of the way, triggering an immune response that destroys tumor cells. NBR1, by contrast, promotes the breakdown of STING and blocks the immune response. Deleting NBR1 from hepatic stellate cells in mice with hepatocellular carcinoma rescues the immune response and shrinks the tumors even when p62 levels remain low.

Reference: Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma, Nishimura, Sadaaki et al. Molecular Cell, Volume 0, Issue 0