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.

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

“…In clinical practice, the emergence of multidrug resistance poses a significant challenge in cancer treatment, particularly in advanced cases of HCC where patients often undergo chemotherapy or targeted therapy [120]. The efficacy of drugs becomes a critical concern in such cases.…”

The current status and future of PD-L1 in liver cancer

“…In addition, HERC2-knocked out hepatocytes limited hepatic PD-L1 expression and improved HCC progression ( 82 ). Heat shock factor 1 (HSF1) up-regulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway ( 83 ). Di (2-ethylhexyl) phthalate (DEHP) might promote the expression of PD-L1 by up-regulating JAK2/STAT3 levels, inhibiting anti-tumor immunity ( 84 ).…”