Boschert Verena, Teusch Jonas, Aljasem Anwar, Schmucker Philipp, Klenk Nicola, Straub Anton, Bittrich Max, Seher Axel, Linz Christian, Müller-Richter Urs D A, Hartmann Stefan
Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, ECTU, University Hospital Würzburg, D-97080 Würzburg, Germany.
Int J Mol Sci. 2020 Nov 20;21(22):8770. doi: 10.3390/ijms21228770.
Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal-epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient's sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC.
头颈部鳞状细胞癌（HNSCC）是一种广泛存在的疾病，生存率低且复发风险高。如今，免疫检查点抑制剂（ICI）治疗已被批准用于HNSCC，作为复发和转移性疾病的一线治疗方法。ICI治疗带来了明显的生存益处，但总体缓解率仍不尽人意。如在不同癌症模型中所示，肝细胞生长因子/间充质-上皮转化（HGF/Met）信号传导促成免疫抑制微环境。因此，我们研究了HNSCC细胞系中HGF与程序性细胞死亡蛋白1（PD-L1）表达之间的关系。临床前数据显示，HGF刺激后可强力诱导PD-L1。进一步分析表明，HGF介导的PD-L1上调依赖于丝裂原活化蛋白激酶。然后我们推测，HGF和可溶性程序性细胞死亡蛋白1（sPD-L1）的血清水平可能是ICI治疗失败的潜在标志物。因此，我们在20例HNSCC患者接受ICI治疗前测定了这些蛋白的血清水平，并将其与治疗结果相关联。重要的是，临床数据显示HNSCC患者血清中这两种血清蛋白（HGF和sPD-L1）呈正相关。此外，ICI无反应患者的sPD-L1血清浓度显著更高。我们的研究结果表明，sPD-L1在HNSCC的ICI治疗中作为预后标志物具有潜在作用。
