A Comprehensive Immune Checkpoint Phenotype Predicts Response and Survival to <scp>PD</scp> ‐1 Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

BACKGROUND: Predictive biomarkers for response to PD-1 blockade in recurrent or metastatic HNSCC remain limited. We investigated whether coordinated expression of multiple inhibitory immune checkpoints defines a clinically relevant biomarker phenotype. METHODS: Clinical and immunohistochemical data from 78 patients with recurrent or metastatic HNSCC treated with nivolumab or pembrolizumab were retrospectively analyzed. Expression of PD-L1, LAG-3, TIM-3, and IDO1 on tumor-infiltrating immune cells was assessed. A composite immune checkpoint phenotype was defined by concurrent immune-cell expression of these markers. Associations with treatment response and survival were analyzed. RESULTS: The composite immune checkpoint phenotype was observed in 10.1% of tumors and was strongly associated with objective response (p < 0.001), disease control (p = 0.006), and improved overall, disease-specific, and progression-free survival (all p ≤ 0.030). In multivariable analysis, this phenotype independently predicted overall (p = 0.031) and disease-specific survival (p = 0.011). CONCLUSION: Coordinated expression of multiple inhibitory immune checkpoints identifies an inflamed tumor microenvironment associated with improved outcomes following PD-1 blockade in HNSCC.