It may soon be feasible to identify which patients suffering from hepatocellular carcinoma, a specific form of liver cancer, could benefit from immunotherapy, as suggested by a preclinical study from Weill Cornell Medicine researchers.
Recent preclinical research conducted by investigators at Weill Cornell Medicine indicates that it might soon be possible to identify which patients with hepatocellular carcinoma could gain from immunotherapy.
The findings, published on Oct. 17 in Molecular Cell, shed light on two proteins, p62 and NBR1, and their contrasting roles in managing the interferon response within hepatic stellate cells. These cells are vital in the liver’s immune response against tumors. The study indicates that elevated levels of the immune-inhibiting NBR1 in these specialized cells might signal patients who are unlikely to benefit from immunotherapy. It also reveals that strategies aimed at reducing NBR1 could help reduce tumor sizes in animal experiments, pointing toward a potential novel treatment for those patients who don’t respond to existing immunotherapy.
“P62 and NBR1 are like yin and yang,” explained Dr. Jorge Moscat, the study’s co-leader and a professor of oncology in pathology, affiliated with the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “When p62 levels are high in hepatic stellate cells, patients are shielded from cancer. Conversely, low levels of p62 can lead to an impaired immune system. If NBR1 levels are elevated, the immune response suffers; however, if NBR1 levels decrease, the immune reaction improves.”
Until recently, treatment options for patients with hepatocellular carcinoma were very limited, providing only a few additional months of life. With the advent of immunotherapy, patients now have a promising alternative that could potentially extend their lives for up to two years.
“The liver is an organ with a significant level of immune suppression,” noted Dr. Maria Diaz-Meco, also a co-leader and a professor of oncology in pathology at Weill Cornell Medicine. “Reactivating the immune system is an appealing strategy that is beginning to show positive outcomes.”
Despite this, not every patient responds to immunotherapy, and only a small fraction achieves lasting remission. At present, it is challenging for clinicians to predict who will benefit. “We require biomarkers to pinpoint which patients will respond positively and who will achieve prolonged survival,” she emphasized.
Drs. Moscat and Diaz-Meco collaborated with co-first authors Dr. Sadaaki Nishimura and Dr. Juan F. Linares, who are engaged as a postdoctoral associate and an instructor, respectively, in the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine, along with Dr. Antoine L’Hermitte, who was formerly affiliated with the Sanford Burnham Prebys Medical Discovery Institute, on this research.
The research team aimed to identify biomarkers and possible therapeutic targets by examining the liver’s dysfunctional healing processes that contribute to cancer. Previous studies have shown that in patients who develop hepatocellular carcinoma, levels of the tumor-suppressing protein p62 are significantly reduced. The new findings highlight that p62 normally aids in triggering an immune response by activating a protein known as STING, which, in turn, removes NBR1 from the equation, setting off an immune response that can eliminate tumor cells. In contrast, NBR1 hinders the immune response by degrading STING. By eliminating NBR1 from hepatic stellate cells in mice, researchers were able to revive the immune response and reduce tumor size, even with low levels of p62.
The research group is currently exploring ways to develop treatments that would eliminate NBR1 in patients and prevent it from interfering with STING. The aim is to reactivate the immune system, thus potentially enhancing the effectiveness of immunotherapy. There are also ongoing developments of drugs designed to activate STING, which might serve as another strategy to boost the immune response in patients with hepatocellular carcinoma. The team will also investigate whether reducing NBR1 could help avert metastasis in various cancer types or prevent tumors from developing resistance to treatment.
Dr. Moscat and Dr. Diaz-Meco intend to further examine the pathways controlling the immune response in the liver.
“It is crucial to fully understand the molecular mechanisms that regulate these processes if we want to advance immunotherapy and comprehend why it works for some patients and not for others,” explained Dr. Diaz-Meco.
Many physicians and scientists at Weill Cornell Medicine collaborate with external organizations to promote scientific progress and provide specialized insight. This institution publicly shares these collaborations to maintain transparency. For further details, please refer to the profiles of Dr. Jorge Moscat and Dr. Maria Diaz-Meco.
This research was supported by the National Cancer Institute, a part of the National Institutes of Health, through various grant numbers including R01CA265892, R01CA250025, R01CA275846, R01CA246765, R01CA277857, R50CA265332, and R50CA283476.
