Spatial single-cell profiling and neighbourhood analysis reveal the determinants of immune architecture connected to checkpoint inhibitor therapy outcome in hepatocellular carcinoma

Histological immune classification in HCC: a pathway to personalized immunotherapy

Immunotherapies targeting exhausted T cells – known as immune checkpoint therapies – have become an established systemic treatment option for advanced hepatocellular carcinoma (HCC) in recent years. However, there is an ongoing debate about whether the underlying etiology of liver disease significantly influences the effectiveness of these treatments. This discussion is largely based on findings from murine models, which suggest that immunotherapies may be less effective in HCC arising from metabolic-associated steatotic liver disease compared to HCC resulting from chronic viral hepatitis. Despite these observations, no definitive therapeutic conclusions have been drawn to date. Furthermore, there are currently no clinically validated predictors to identify patients who are likely to respond to immunotherapy. The study by Salié et al. presents a histological immune classification of HCC which distinguishes tumors – regardless of the underlying liver disease – into 3 categories: immune-enriched, immune-depleted, and compartmentalized (an intermediate phenotype). This classification was identified and validated through high-dimensional immunological tissue analyses of tumor tissue from HCC patients. The study not only quantified individual immune cell populations within the tumor tissue but also examined their cell-cell interaction profiles. The clinical relevance of this classification lies in a simplified histological characterization of the CD8 T-cell infiltrate. Tumors with an enriched immune infiltrate showed significantly better responses to immune checkpoint therapy compared to immune-depleted tumors. The simplicity of the histological evaluations required for this classification makes this approach immediately applicable for guiding therapeutic decisions in molecular tumor boards. Thus, the histological confirmation of an HCC, which is recommended in clinical guidelines but not always rigorously implemented, gains new relevance. This classification underscores the value of targeted histopathological evaluation of the tumor immune infiltrate. For example, early prioritization of immunotherapy could be considered for patients with immune-enriched tumors. However, further prospective studies are needed to validate these findings. Moving forward, the immunological classification of the tumor microenvironment should be considered in the evaluation of clinical phase 3 trials involving checkpoint inhibitors.