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Published on: April 22, 2019
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.
Abstract:
Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma, yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T-cell function, the specific role of secreted ISG15 in T-cell exhaustion remains unclear. In this study, we report that the analysis of human OSCC datasets revealed significant enrichment of the ISG core score, including ISG15, in tumors compared with adjacent nontumor tissues. Using an in vitro model of human T-cell dysfunction, we found that acute ISG15 exposure enhanced CD8+ T-cell effector functions, whereas prolonged exposure induced severe dysfunction via a CD11a/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Moreover, PD-1 blockade treatment significantly slowed tumor progression and restored T-cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T-cell dysfunction, but these cells remain responsive to PD-1 blockade. Furthermore, this study identifies ISG15 as a potential biomarker for identifying patients who are likely to benefit from PD-1 blockade therapy.
Insights
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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