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Chronic ISG15 Exposure Accelerates CD8 T Cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma

ABSTRACT: Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), but clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), associated with oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. While chronic interferon signaling impairs CD8 T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analyzing human OSCC datasets, we observed significant enrichment of the ISG core score, including ISG15, in tumors compared to adjacent non-tumor tissues. Using a novel in vitro model of human T cell dysfunction, we found that acute ISG15 exposure enhances CD8 T cell effector functions, whereas prolonged ISG15 exposure induces severe dysfunction via an endocytic mechanism independent of LFA-1 signaling. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8 T cells though these cells were dysfunctional. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell functionality in ISG15-expressing tumors. Our findings indicate that chronic ISG15 exposure promotes CD8 T cell dysfunction; however, these cells remain responsive to PD-1 blockade. This study reveals ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297506 | GEO | 2025/08/10

REPOSITORIES: GEO

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Chronic ISG15 Exposure Accelerates CD8 T Cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma

Project description:Chronic ISG15 Exposure Accelerates CD8 T Cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma

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2023-04-19 | PXD040957 | Pride

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma

Project description:<h4><strong>OBJECTIVE:</strong> Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc-, a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC).</h4><p><strong>METHODS:</strong> qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+/NADPH dynamics were measured using a NADP+/NADPH kit.</p><p><strong>RESULTS:</strong> In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis.</p><h4><strong>CONCLUSIONS:</strong> System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.</h4>

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