Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy

Abstract

Locoregional therapies (LRTs) of hepatocellular carcinoma (HCC) represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC. Among these, TACE is used throughout the stage Ib to IIIb of HCC treatment. In recent years, immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research. At the same time, targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC, and their clinical application has been quite mature. HCC is the sixth most common malignant tumor in the world. When it comes to its treatment, different therapies have different indications, and their individual efficacies are not satisfactory, which makes the exploration of the use of combination therapy in HCC treatment become a new trend. In this paper, the status of the three therapies and the progress of their combined application are briefly reviewed.

Keywords: Combination therapy; Hepatocellular carcinoma; Immunotherapy; Locoregional therapy; Targeted therapy.

Fig. 1

LRT, immunotherapy and targeted therapy can produce synergistic effects in a variety of ways. TACE and ablation lead to tumor necrosis, enabling effector T cells to activate, recognize, and kill tumors. RFA can induce epithelial mesenchymal transformation (EMT) of tumor cells, and sorafenib can inhibit this effect. Local VEGF levels are elevated following TACE, thus anti-VEGF drugs may play a counter role. Following TACE, tumor hypoxia and PD1/PDL1 expression are increased, which provides an opportunity for anti-PD1 therapy; RFA has similar effects. In addition, the combination of LRTs and anti-PD1 therapy can reduce the aggregation of myeloid-derived suppressor cell (MDSCs) and the proportion of Tregs. Targeted drugs can also promote the activation and aggregation of DCs, while anti-CTLA-4 therapy can remove the inhibition of the antigen presentation process, enabling T cells to fully play their role. Immune checkpoint inhibitors can activate functionally depleted T cells and restore the tumoricidal effect of T cells by blocking the corresponding pathway-mediated immunosuppressive response. Anti-VEGF drugs can cause blood vessel normalization, inhibit VEGF signaling pathways, restore DC function, enhance the infiltration and function of immune cells, and reduce the infiltration of Tregs.