HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma

Abstract

Hepatocellular cancer (HCC) is a serious illness with high prevalence and mortality throughout the whole world. For advanced HCC, immunotherapy is somewhat impactful and encouraging. Nevertheless, a substantial proportion of patients with advanced HCC are still unable to achieve a durable response, owing to heterogeneity from clonal variability and differential expression of the PD-1/PD-L1 axis. Recently, heat shock factor 1 (HSF1) is recognized as an important component of tumor immunotherapeutic response as well as related to PD-L1 expression in cancer. However, the mechanism of HSF1 regulating PD-L1 in cancer, especially in HCC, is still not fully clear. In this study, we observed the significantly positive correlation between HSF1 expression and PD-L1 expression in HCC samples; meanwhile combination expressions of HSF1 and PD-L1 served as the signature for predicting prognosis of patients with HCC. Mechanistically, HSF1 upregulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway in HCC. In addition, we explored further the potential values of targeting the HSF1-APOJ-STAT3 axis against CD8⁺ T cells-mediated cancer cells cytotoxicity. These findings unveiled the important involvement of HSF1 in regulating PD-L1 expression in HCC as well as provided a novel invention component for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade.

Keywords: APOJ; HSF1; Hepatocellular carcinoma; JAK/STAT3; PD-L1; immunotherapy.

Figure 1.

A positive association between HSF1 expression and PD-L1 expression in HCC including cancer tissues and cell lines, showing HSF1 downregulation leading to the downregulation of PD-L1 expression.

Figure 2.

The regulation of HSF1 on PD-L1 expression requires the involvement of CD8 + T signature-related APOJ, showing a positive correlation between APOJ expression and abundance of CD8 + T cells in HCC.

Figure 3.

STAT3 signaling as a downstream of APOJ contributes to HSF1-induced PD-L1 expression in HCC, reflecting by the effects of HSF1 or APOJ on the levels of p-STAT3/STAT3.

Figure 4.

Targeting intervention on HSF1-APOJ-STAT3 axis affects CD8 + T cells-mediated cytotoxicity for HCC cells by using the specific inhibitor in vitro.