The prognostic role of NK cells and their ligands in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis

Background: Despite the improvement in therapeutic interventions, 5-year survival rates in Head and Neck Squamous Cell Carcinoma (HNSCC) are limited. HNSCC is an immunogenic cancer type for which molecular stratification markers are lacking. Tumor-infiltrating lymphocytes (TILs) have shown a favorable prognostic role in different cancer types. This study focused on the prognostic role of NK cells in HNSCC. Methods: A systematic search was conducted in Pubmed/Medline and Embase. Articles that correlated the presence of intratumoral NK cells, activating/inhibiting receptors, death receptors, or their ligands with clinicopathologic characteristics or survival were included. A meta-analysis was performed that assessed the association between CD56+ and CD57+ and overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Results: A pooled analysis indicated a favorable prognostic role of CD56+ and CD57+ NK cells for OS (HR 0.19 CI 0.11–0.35). NK cell markers NKp46 and Granzyme B (GrB) also have a favorable prognostic role. NK cell ligand Fas correlated with better survival and better characteristics. NK cell marker Fas-L, NK cell ligands CEACAM1, RCAS1, CD70 and TRAIL-R, and effector molecules of these ligands, FADD and FAP1, correlated to features of worse prognosis. Conclusion: A favorable prognostic role of NK cells in HNSCC was found in this review. Some studies implied the opposite, indicating the fine balance between pro- and anti-tumor functions of NK cells. Future studies using homogeneous patient cohorts regarding tumor subsite and treatment modality, are necessary to further provide insight into the prognostic role of NK cells.