BACKGROUND: The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be 
significantly involved in T-cell regulation. Recent studies suggest that PD-L1 
expression in malignant tumors contributes to an immunosuppressive 
microenvironment and disruption of antitumoral immune response. Drugs targeting 
this pathway are already tested in clinical trials against several tumor 
entities with promising results. However, until now comprehensive data with 
regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma 
(HNSCC) is still lacking.
PATIENTS AND METHODS: We assessed PD-L1 and PD-L2 expression via 
immunohistochemistry in two independent cohorts of 293 HNSCC patients.
RESULTS: A significant subset of HNSCC showed high expression levels of PD-L1. 
Most remarkable, we detected a strong correlation between PD-L1 expression and 
overall survival time in both HNSCC cohorts. Further, in multivariate cox 
proportional hazard models, PD-L1 dominates as the strongest prognostic factor 
of patient's outcome in HNSCC, leaving even tumor stage and distant metastasis 
behind. Moreover, strong PD-L1 expression was associated with the presence of 
distant metastases in a subset of cases.
CONCLUSIONS: In summary, while the significance of PD-L2 in HNSCC seems to 
minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a 
both robust and strong prognostic biomarker. In this respect, our results 
provide hints on further application of therapies targeting the PD-1/PD-L1 
pathway in HNSCC. Investigation of response and outcome of patients receiving 
anti-PD-1/PD-L1 containing therapies in correlation with PD-L1 expression 
analysis should be an important task for the future.
STATEMENT OF TRANSLATIONAL RELEVANCE: In spite of improved treatment options and 
increasing knowledge of molecular alterations in HNSCC, the survival rate has 
not been dramatically changed in the past decades. Pies are missing in HNSCC. 
One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 
or its receptor PD-1 are subject of several clinical studies in different cancer 
entities. However, comprehensive data about PD-L1 expression in HNSCC and 
therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. 
Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major 
localizations. We observed a strong correlation between expression of PD-L1 and 
reduced overall survival time. Furthermore, high PD-L1 expression was identified 
as a strong prognostic factor of patient's outcome when verified together with 
recognized prognostic factors.