Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: During 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. ABSTRACT: 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.