Current clinical knowledge surrounding one of the most promising immune checkpoint pathways, namely programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2, is reviewed in the context of head and neck squamous cell carcinoma. The results of two phase III clinical trials (KEYNOTE 040 and CheckMate 141) are critically examined. The utility of predictive biomarkers of response to immune checkpoint blockade, such as PD-L1/PD-L2 protein expression, interferon-gamma gene expression signatures, and mutational and neoantigen load, is discussed. Finally, we project future directions in the immuno-oncology field by discussing other promising predictive biomarkers as well as areas where the next advances are likely to take place, such as in the implementation of immune checkpoint inhibitors earlier in the course of cancer treatment and/or in combination therapies.

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