Liver cancer is the fourth leading cause of cancer-related deaths and its incidence is on the rise, with one million new cases projected annually in 2025. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. For the treatment of patients with advanced HCC, sorafenib was approved in 2007, but recently immune checkpoint inhibitors (atezolizumab + bevacizumab), which promote the ability of the immune system to fight cancer, have become the standard systemic therapies.
Our article published in Nature shows that checkpoint inhibitors are significantly less effective in patients with non-viral compared to viral-related HCC. We explored the most common non-viral etiology, non-alcoholic steatohepatitis (NASH), associated to overweight and diabetes. We identified a specific population of dysfunctional resident T cells (activated CD8+PD1+CxCR6 T cells) which drive NASH progression and are the primary mechanism of resistance to immunotherapies in murine models of NASH-HCC and in human NASH (Fig 1). In addition, through a meta-analysis of three randomized phase III clinical trials testing inhibitors immunotherapies in 1,600 patients with advanced HCC, we identified that these therapies are significantly more effective in viral-related HCC compared to non-viral etiologies.