A preclinical study by Weill Cornell Medicine researchers suggests that it may soon be possible to predict which patients with hepatocellular carcinoma, a form of liver cancer, will respond to immunotherapy.
Published Oct. 17 in Molecular Cell, the study puts the spotlight on two proteins, p62, and NBR1, along with their roles in liver cancer. These proteins regulate the interferon response in HSCs and are crucial for liver immune defense against tumors. With such an approach, researchers identified the high expression of NBR1 in these cells as a biomarker that signals a poor likelihood of response to immunotherapy. They went further to show in animal models the knockdown of NBR1 reduced tumor growth-a potential new treatment option for patients insensitive to standard therapies.
“p62 and NBR1 are like yin and yang,” said Dr. Jorge Moscat, one of the lead investigators on the study. “It’s high in hepatic stellate cells, protective against cancer, but if it’s low, it disables the immune system. On the other hand, when NBR1 is high, the immune system is impaired, whereas when NBR1 is low, the immune response is enhanced.“
Until recently, there were few treatment options for patients with hepatocellular carcinoma, and the treatments that were available extended life by only a few months. Immunotherapy has given these patients new hope in extending life up to two years.
“The liver is highly immune-suppressed,” said Dr. Maria Diaz-Meco, co-principal investigator. “Reactivating the immune system is a very promising approach, and we are starting to see results.”
However, it remains the case that not all patients respond to immunotherapy, and only a small number achieve long-term remission. At the moment, there is no way for doctors to predict which ones will benefit from the therapy. “We need biomarkers to determine who will respond and who will survive long-term,” Dr. Diaz-Meco said.
Drs. Moscat and Diaz-Meco carried out the study with co-first authors Dr. Sadaaki Nishimura and Dr. Juan F. Linares. They wanted to understand how to identify biomarkers and therapeutic targets by studying what goes wrong in the liver’s healing processes leading to cancer. Previous studies have already demonstrated that levels of p62 were often low in patients who develop hepatocellular carcinoma. The new study found that p62 turns on a protein, called STING, which in turn pushes NBR1 aside, unleashing an immune cascade that kills cancer cells. NBR1, on the other hand, suppresses STING, shutting down the immune system.
By knocking out NBR1 in hepatic stellate cells in mice, the researchers could reinstate the immune response. And reduce tumor growth, even when levels of p62 were low.
The team is now working on the development of therapies that would deplete NBR1 levels in patients. Thus promoting immune responses. They are also developing drugs that activate STING; such drugs may eventually increase further the effectiveness of immunotherapy. The researchers will proceed to examine precisely how NBR1 promotes spread and treatment resistance.
The work of Drs. Moscat and Diaz-Meco will likely lead not only to better treatments. But also to a better understanding of how to improve the results in immunotherapy for liver cancer patients.
ANI
