Survival and Tumour Microenvironment in Spatially Distinct Regions in Patients Resected for Hepatocellular Carcinoma: A Multicentre Study

The tumour microenvironment (TME) may play a pivotal role in the development, progression, and prognosis of HCC. We aimed to investigate the prognostic association of the TME in Danish liver-resected patients with HCC. We included all patients liver-resected for HCC between January 2000 and December 2016 with available tumour tissue stored in the diagnostic biobank. Resected tumour tissues and corresponding normal liver tissues were investigated for immune cell densities with immunohistochemistry. We investigated the association between individual immune cell densities and prognosis. We identified distinct patient groups based on hierarchical clustering and heatmap visualisation, for their association with prognosis. We included 75 patients, 72% were male and median age was 66 years (58-72). Most patients had a single tumour, median size was 50 mm, and 57% without vascular invasion. Median follow-up was 44 months and 50% of the patients had a recurrence within the study period. The density of CD4+ T cells in the invasive margin was significantly associated with a higher risk of mortality (HR = 1.43, 95% CI: 1.13–1.82), whereas a higher density of tumour-associated macrophages in the tumour centre was significantly associated with a lower risk of cancer-related mortality (HR = 0.53, 95% CI: 0.28–1.00). Clustering of patients based on immune cell densities in tumour tissue revealed that those with lower immune cell counts exhibited significantly worse disease-free survival when compared to other patients (p= 0.03). The TME had a prognostic association with survival, lending credence to spatial immune cell densities as important factors contributing to prognosis.