Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Shanghai, People's Republic of China.
Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Guangxi, China.
Cancer Biol Ther. 2023 Dec 31;24(1):1-9. doi: 10.1080/15384047.2022.2156242.
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.
肝细胞癌（HCC）是一种全球性的严重疾病，其发病率和死亡率都很高。对于晚期 HCC，免疫疗法具有一定的影响力和令人鼓舞的作用。然而，由于克隆变异性和 PD-1/PD-L1 轴表达的差异，相当一部分晚期 HCC 患者仍然无法获得持久的反应。最近，热休克因子 1（HSF1）被认为是肿瘤免疫治疗反应的一个重要组成部分，并且与癌症中的 PD-L1 表达有关。然而，HSF1 调节癌症中 PD-L1 的机制，特别是在 HCC 中，仍不完全清楚。在这项研究中，我们观察到 HCC 样本中 HSF1 表达与 PD-L1 表达之间存在显著的正相关；同时，HSF1 和 PD-L1 的共同表达可作为预测 HCC 患者预后的标志物。在机制上，HSF1 通过诱导 APOJ 表达并激活 HCC 中的 STAT3 信号通路而上调 PD-L1 表达。此外，我们进一步探讨了靶向 HSF1-APOJ-STAT3 轴对 CD8 T 细胞介导的癌细胞细胞毒性的潜在价值。这些发现揭示了 HSF1 在调节 HCC 中 PD-L1 表达中的重要作用，并为提高 PD-1/PD-L1 阻断的临床反应率和疗效提供了一个新的发明成分。
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