Immunotherapy is not only significantly less effective in patients with liver cancer who previously had nonalcoholic steatohepatitis, but it actually may fuel tumor growth, according to a study published by Pfister et al in Nature.
Nonalcoholic steatohepatitis affects as many as 40 million people worldwide and is associated with obesity and diabetes.
Meta-analysis Findings
The researchers led a large international collaboration to investigate immunotherapy’s effect on hepatocellular carcinoma. They conducted a meta-analysis of three randomized phase III human trials that tested immunotherapy in over 1,600 patients with hepatocellular carcinoma, and found that in nonviral cases, such as nonalcoholic steatohepatitis–related hepatocellular carcinoma, therapy was significantly less effective than in viral-related cases.
In addition, researchers found that in animal models, anti–PD-1 therapies actually led to tumor growth instead of the intended effect of aiding the immune system to kill cancer cells and shrink the tumor. In these models, researchers identified CD8-positive, PD-1–positive immune cells as drivers of these phenomena. These cells were found to be dysfunctional and incapable of immunosurveillance.
Josep Llovet, MD, PhD
“In addition to allowing clinicians to optimize treatment protocols based on the underlying liver disease, the knowledge obtained through this study will provide a backbone for the design of further combination treatments to overcome current limitations and improve survival for patients with these underlying liver conditions,” said senior and co-corresponding author Josep Llovet, MD, PhD, Founder and Director of the Liver Cancer Program at The Tisch Cancer Institute and Professor of Medicine (Liver Diseases) at the Icahn School of Medicine at Mount Sinai. “These results also highlight the need for refined therapeutic strategies aimed at treating both the tumor as well as the microenvironment associated with distinct underlying liver disease.”
Nonalcoholic fatty liver disease, a condition that is a precursor of nonalcoholic steatohepatitis, is estimated to affect 25% of the population worldwide, and up to 20% of these patients will progress to having nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis is an emerging risk factor for hepatocellular carcinoma, which led to this study’s investigation of immunotherapy’s effects on nonalcoholic steatohepatitis–related hepatocellular carcinoma. While immunotherapy has clinical benefit for hepatocellular carcinoma, this study’s findings are important because a quarter of all patients with hepatocellular carcinoma also have nonalcoholic steatohepatitis.
The study authors concluded, “Collectively, these data show that nonviral hepatocellular carcinoma, and particularly nonalcoholic steatohepatitis–related hepatocellular carcinoma, might be less responsive to immunotherapy, probably owing to nonalcoholic steatohepatitis–related aberrant T-cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with hepatocellular carcinoma according to underlying etiology in studies of immunotherapy as a primary or adjuvant treatment.”
Disclosure: For full disclosures of the study authors, visit nature.com.
