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Updated: Nov 12, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas
Lucas V Dos Santos1, Carina M Abrahão1, William N William1
1Centro de Oncologia, Hospital BP, A Beneficência Portuguesa de São Paulo, São Paulo, Brazil.
Abstract:
Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.
Insights
Head and neck squamous cell carcinomas (HNSCC) can resist immunotherapy. This review explores resistance mechanisms and strategies to improve anti-PD-1 therapy effectiveness in HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Head and neck squamous cell carcinomas (HNSCC) can evade immune surveillance through mechanisms like programmed death ligand-1 (PD-L1) expression.
- PD-L1 is the current biomarker for selecting HNSCC patients for anti-PD-1 therapy, but it incompletely predicts treatment response.
- Many HNSCC patients do not respond to anti-PD-1 therapy due to de novo resistance, and others develop acquired resistance.
Purpose of the Study:
- To provide an overview of the immune landscape in HNSCC.
- To summarize the clinical activity of PD-1/PD-L1 axis inhibitors in HNSCC.
- To review mechanisms of de novo and acquired resistance to immunotherapy in HNSCC and discuss novel strategies to overcome this resistance.
Main Methods:
- Review of preclinical and clinical studies on HNSCC immunology and immunotherapy.
- Analysis of biomarkers for anti-PD-1 therapy benefit in HNSCC.
- Examination of mechanisms underlying resistance to immune checkpoint inhibitors.
Main Results:
- PD-L1 expression is a limited biomarker for predicting response to anti-PD-1 therapy in HNSCC.
- Multiple mechanisms contribute to both de novo and acquired resistance to immunotherapy in HNSCC.
- Current understanding of resistance mechanisms is incomplete, necessitating further research.
Conclusions:
- Overcoming resistance to immune checkpoint inhibitors is crucial for improving HNSCC treatment outcomes.
- Novel therapeutic strategies are under investigation to enhance the efficacy of immunotherapy in HNSCC.
- A deeper understanding of the HNSCC immune landscape is essential for developing more effective treatments.
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