Mechanisms of Resistance and Therapeutic Perspectives in Immunotherapy for Advanced Head and Neck Cancers

Immunotherapy is emerging as an effective treatment for advanced head and neck cancers and interest in this treatment modality has led to rapid expansion of this research. Pembrolizumab and nivolumab, monoclonal antibodies directed against the programmed cell death-1 (PD-1) receptor, are US Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved immunotherapies for head and neck squamous cell carcinoma (HNSCC). Resistance to immunotherapy is common, with about 60% of patients with recurrent or metastatic HNSCC not responding to immunotherapy and only 20–30% of patients without disease progression in the long term. Overcoming resistance to immunotherapy is therefore essential for augmenting the effectiveness of immunotherapy in HNSCC. This review details the innate and adaptive mechanisms by which head and neck cancers can become resistant to immunotherapeutic agents, biomarkers that can be used for immunotherapy patient selection, as well as other factors of the tumor microenvironment correlated with therapeutic response and prognosis. Numerous combinations and novel immunotherapies are currently being trialed, based on better understood immune evasion mechanisms. These potential treatments hold the promise of overcoming resistance to immunotherapy in head and neck cancers.