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Published on: April 22, 2019
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Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral
Yu-Lin Chen1,2, Amir Yousif1,3, Chung-Hsing Chen2,4
1Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio.
Cancer Immunology Research
|August 29, 2025
Summary
Interferon-stimulated gene 15 (ISG15) promotes T cell exhaustion in head and neck cancers. However, these exhausted T cells remain responsive to PD-1 blockade immunotherapy, suggesting ISG15 as a predictive biomarker.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immunotherapy shows promise for head and neck squamous cell carcinoma (HNSCC), but limited responses are observed.
- Elevated interferon-stimulated gene 15 (ISG15) expression in oral squamous cell carcinoma (OSCC) may hinder treatment efficacy.
- The role of secreted ISG15 in T cell exhaustion, a key factor in immunotherapy resistance, is not fully understood.
Purpose of the Study:
- To investigate the specific role of secreted ISG15 in CD8+ T cell dysfunction and its impact on HNSCC immunotherapy.
- To determine if ISG15-impaired T cells retain responsiveness to PD-1 blockade therapy.
- To evaluate ISG15 as a potential biomarker for predicting immunotherapy response in HNSCC.
Main Methods:
- Analysis of human OSCC datasets for ISG15 enrichment.
- Development of a novel in vitro model of human T cell dysfunction.
- Utilizing an immunocompetent orthotopic OSCC mouse model.
- Assessing the effects of ISG15 exposure on CD8+ T cell function and tumor growth.
- Evaluating the efficacy of PD-1 blockade in ISG15-expressing tumors.
Main Results:
- ISG15 was significantly enriched in OSCC tumors compared to non-tumor tissues.
- Prolonged ISG15 exposure induced CD8+ T cell dysfunction via an endocytosis-dependent mechanism.
- ISG15-expressing OSCC tumors showed accelerated growth and recruited functionally impaired CD8+ T cells.
- PD-1 blockade significantly slowed tumor progression and restored T cell function in the presence of ISG15.
Conclusions:
- Chronic ISG15 exposure promotes CD8+ T cell dysfunction in HNSCC.
- ISG15-impaired T cells remain responsive to PD-1 blockade therapy.
- ISG15 is a potential biomarker for identifying HNSCC patients who may benefit from PD-1 blockade.
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