The association between tumour heterogeneity and immune evasion mechanisms in hepatocellular carcinoma and its clinical implications

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The emergence of combination therapy, atezolizumab (anti-PDL1, immune checkpoint inhibitor) and bevacizumab (anti-VEGF) has revolutionised the management of HCC. Despite this breakthrough, the best overall response rate with first-line systemic therapy is only about 30%, owing to intra-tumoural heterogeneity, complex tumour microenvironment and the lack of predictive biomarkers. Many groups have attempted to classify HCC based on the immune microenvironment and have consistently observed better outcomes in immunologically "hot" HCC. We summarised possible mechanisms of tumour immune evasion based on the latest literature and the rationale for combination/sequential therapy to improve treatment response. Lastly, we proposed future strategies and therapies to overcome HCC immune evasion to further improve treatment outcomes of HCC.

Fig. 1. Tumour immune microenvironment alterations post transarterial chemoembolisation versus Y-90 radioembolisation.

TACE transarterial chemoembolisation, TARE transarterial radioembolisation, Y-90 yttrium-90, SIRT selective internal radiation therapy, PBMC peripheral blood mononuclear cells, HIF hypoxia-induced factors, Treg regulatory T cells, DCs dendritic cells, Tex exhausted T cells, NK cell natural killer cell, GZB granzyme B, APCs antigen-presenting cells, ROS reactive oxygen species.

Fig. 2. Strategic approaches for overcoming immune evasion mechanisms in Hepatocellular Carcinoma (HCC) involve transforming the immune cold tumour microenvironment (TME) into an immune hot TME.

Additionally, efforts focus on converting immunosuppressive, pro-tumour TME into an effective, anti-tumour immune hot TME. Treg regulatory T cell, NK cell natural killer cell, cDC conventional dendritic cell, pDC plasmacytoid dendritic cell, CAR T chimeric antigen receptor T cell, TCR T T cell receptor T cell.