Abstract
Simple SummaryDuring the last decades, scientific advances in immuno-oncology and a better understanding of tumors’ immune profile led to the development of novel immunotherapeutic strategies, especially immune checkpoint inhibitors. The blockade of PD-1 by monoclonal antibodies (mAbs) is the only immunotherapy based on immune checkpoint pathways approved for head and neck squamous cell carcinoma. As only a small fraction of patients perceives clinical benefit, understanding the molecular mechanisms and signaling pathways activated by the immune checkpoints and other tumor intrinsic features that modulate the immune infiltrate is crucial to better select patients for immunotherapy treatment and to develop novel therapeutic strategies. We here review the immune escape mechanisms of head and neck tumors, with a particular focus on the immune checkpoints, their role as therapeutic targets, and the predictive biomarkers of response to anti-PD-1/PD-L1 therapy. We also summarize the ongoing clinical trials testing several combinations of immune checkpoint inhibitors with other therapeutic approaches to improve patient outcomes.Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors usually diagnosed at an advanced stage and characterized by a poor prognosis. The main risk factors associated with its development include tobacco and alcohol consumption and Human Papillomavirus (HPV) infections. The immune system has a significant role in the oncogenesis and evolution of this cancer type. Notably, the immunosuppressive tumor microenvironment triggers immune escape through several mechanisms. The improved understanding of the antitumor immune response in solid tumors and the role of the immune checkpoint molecules and other immune regulators have led to the development of novel therapeutic strategies that revolutionized the clinical management of HNSCC. However, the limited overall response rate to immunotherapy urges identifying predictive biomarkers of response and resistance to treatment. Here, we review the role of the immune system and immune checkpoint pathways in HNSCC, the most relevant clinical findings linked to immunotherapeutic strategies and predictive biomarkers of response and future treatment perspectives.
Highlights
Head and neck cancers comprise a heterogeneous group of tumors arising in the head and neck region, with head and neck squamous cell carcinoma being the most frequent histology type
The major immune checkpoint pathways implicated in Head and neck squamous cell carcinoma (HNSCC) immunosuppression are progressive disease (PD)-1/Programmed Death-Ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), the T-cell immunoglobulin mucin 3 (TIM-3), the lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (TIGIT) (Figure 1)
Among the several mechanisms implicated in immune evasion, the expression of different immune checkpoint pathways has been of great interest due to the development of novel immunotherapeutic strategies targeting these pathways, which revolutionized the treatment of solid tumors, including HNSCC
Summary
Head and neck cancers comprise a heterogeneous group of tumors arising in the head and neck region, with head and neck squamous cell carcinoma being the most frequent histology type. Around 50% of patients with locally advanced HNSCC develop recurrence after primary treatment with metastatic, local, or regional disease and have a poor prognosis with a median overall survival (OS) under 12 months (six to nine months without treatment) [1]. Treatment of these patients is complex and requires the evaluation of tumor- and patient-related factors for selecting the optimal combination and sequencing of treatments. We discuss the use of Immune Checkpoint Blockade (ICB) in HNSCC treatment, the ongoing clinical trials testing several combinations of immune checkpoint inhibitors with other therapeutic approaches, and novel predictive biomarkers of response to anti-PD-1/PD-L1 therapy
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