Shuyu pills inhibit immune escape and enhance chemosensitization in hepatocellular carcinoma

ARTICLE HIGHLIGHTS

Research background

Hepatocellular carcinoma (HCC) is characterized by dysregulation of the immune microenvironment and the development of chemoresistance. The latest research shows that the simultaneous inhibition of hypoxia-inducible factor-1 alpha (HIF-1α) and programmed cell death protein 1 (PD-1) has the potential to enhance the hosts antitumour immunity. Moreover, inhibition of the PD-1/programmed cell death 1 ligand 1 (PD-L1) axis may mitigate tumour chemoresistance.

Research motivation

Shuyu pills (SYPs) contain immunity-enhancing and antitumour components, making them a potential HCC treatment. The motivation of this research was to study the effect and mechanism of SYPs on HCC.

Research objectives

To investigate the efficacy of SYPs for HCC treatment via simultaneous HIF-1α and PD-L1 inhibition and the mechanism involved.

Research methods

The subcutaneous xenograft tumours model was established in BALB/c nude mice. The male mice (male, 5 weeks old; n = 24) were then randomly divided into the four groups (n = 6): Control group (0.9% normal saline), SYP group (200 mg/kg), SYP + cisplatin (DDP) group (200 mg/kg + 5 mg/kg weekly via intraperitoneal injection), and DDP group (5 mg/kg weekly via intraperitoneal injection). The tumour volumes and body weights of the mice were measured every 2 d. The mice were euthanized by cervical dislocation after 14 d of continuous treatment, and the xenograft tissues were excised and weighed. The western blot assay was used to measure the protein expression of HIF-1α, PD-1, PD-L1, CD4+ T cells, and CD8+ T cells in the HCC tumours from the mice. Quantitative reverse transcription polymerase chain reaction a was used for the real-time quantitative detection of PD-1, PD-L1, and HIF-1α mRNA expression. The immunofluorescence assay was conducted to examine the expression of CD4+ T cells and CD8+ T cells.

Research results

Compared with the mice in the control group, those in the SYP and SYP + DDP groups had lower tumour volumes and tumour weights. Moreover, the protein and mRNA expressions of the oncogene HIF-1α and that of the negative immunomodulatory factors PD-1 and PD-L1 were decreased in both the SYP and SYP + DDP groups, with the decrease effects being more prominent in the SYP + DDP group than in the SYP group. Additionally, the quantitative and protein expressions of CD4+ T cells and CD8+ T cells were simultaneously upregulated in the SYP + DDP group, whereas only the expressions of CD4+ T cells were upregulated in the SYP group. Finally, the expression of HIF-1α was found to be positively correlated with that of PD-1/PD-L1 and negatively correlated with the expression of the CD4+ T cells and CD8+ T cells.

Research conclusions

SYPs inhibit immune escape and enhance chemosensitization in HCC via simultaneous inhibition of HIF-1α and PD-L1, thus inhibiting the growth of subcutaneous xenograft tumours with HCC.

Research perspectives

SYPs inhibit immune escape and enhance chemosensitization in HCC. It is a potential adjuvant drug for the treatment of HCC.