Notch1 Mutation Represents a Potential Therapeutic Target to Enhance Immune Recognition in Oral Squamous Cell Carcinoma

IF 1.9 Q4 ONCOLOGY

Cancer reports Pub Date : 2025-09-30 DOI:10.1002/cnr2.70345

Takahiro Iwamoto, Kazuhiro Ogi, Takafumi Nakagaki, Takashi Sasaya, Sho Miyamoto, Koyo Nishiyama, Kenta Sasaki, Shintaro Sugita, Yasushi Sasaki, Akihiro Miyazaki

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Abstract

Background

Notch1, a tumor suppressor gene, is one of the most frequently mutated genes in head and neck squamous cell carcinoma (HNSCC). Therefore, it is clinically important to investigate the effects of Notch1 mutations on antitumor immunity in oral squamous cell carcinoma (OSCC), a subset of HNSCC.

Aims

This study investigated Notch1 mutations and the expression of immune-related proteins. We also examined the influence of Notch1 mutations on the immune microenvironment using a public database.

Methods and Results

We examined the expression of Notch1–4 in OSCC cell lines using qPCR. After Notch1 knockdown, OSCC cell proliferation and migration were analyzed using CCK8 and wound healing assays, respectively. Localization of programmed cell death ligand 1 (PD-L1) was assessed by western blot and flow cytometry, while PD-L1 expression was evaluated by western blot. In the somatic mutation analysis of 47 OSCC patients, the relationship between tumor-infiltrating CD8⁺ T cells and PD-L1 expression was analyzed using immunohistochemical (IHC) staining. Furthermore, data from The Cancer Genome Atlas (TCGA) were analyzed using multiple online bioinformatics tools to compare the characteristics of Notch1 mutations in HNSCC. The expression of Notch1 varied depending on the OSCC cell line phenotype, and Notch1 mutation was significantly correlated with tumor growth but not with tumor infiltration. In Notch1 knockdown, PD-L1 expression on the tumor cell surface increased, while cytoplasmic PD-L1 expression decreased. Among the 47 OSCC patients analyzed, seven (14%) had Notch1 mutations. Of those, five patients (71%) exhibited high tumor-infiltrating CD8⁺ T cells and Notch1 mutation. Online bioinformatics analysis using the xCell algorithm revealed that Notch1-mutated tumors had significantly higher levels of naïve CD8⁺ T cells compared to Notch1 wild-type tumors.

Conclusion

These findings highlight Notch1 mutation as a potential therapeutic target for immune recognition in OSCC.

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Notch1突变是增强口腔鳞状细胞癌免疫识别的潜在治疗靶点

Notch1是一种肿瘤抑制基因，是头颈部鳞状细胞癌（HNSCC）中最常见的突变基因之一。因此，研究Notch1突变对口腔鳞状细胞癌（OSCC）抗肿瘤免疫的影响具有重要的临床意义。目的研究Notch1基因突变与免疫相关蛋白的表达。我们还使用公共数据库检测了Notch1突变对免疫微环境的影响。方法与结果采用qPCR方法检测Notch1-4在OSCC细胞株中的表达。Notch1敲除后，分别用CCK8和伤口愈合实验分析OSCC细胞的增殖和迁移。western blot和流式细胞术检测程序性细胞死亡配体1 （PD-L1）的定位，western blot检测PD-L1的表达。在47例OSCC患者的体细胞突变分析中，采用免疫组化（IHC）染色分析肿瘤浸润性CD8+ T细胞与PD-L1表达的关系。此外，利用多种在线生物信息学工具分析了来自癌症基因组图谱（TCGA）的数据，比较了HNSCC中Notch1突变的特征。Notch1的表达随OSCC细胞系表型的变化而变化，Notch1突变与肿瘤生长显著相关，而与肿瘤浸润不相关。Notch1敲低后，肿瘤细胞表面PD-L1表达升高，细胞质内PD-L1表达降低。在分析的47例OSCC患者中，7例（14%）有Notch1突变。其中，5名患者（71%）表现出高肿瘤浸润性CD8+ T细胞和Notch1突变。使用xCell算法的在线生物信息学分析显示，与Notch1野生型肿瘤相比，Notch1突变肿瘤的naïve CD8+ T细胞水平显著升高。结论Notch1突变是OSCC免疫识别的潜在治疗靶点。

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