Head and neck squamous cell carcinoma (HNSCC) shows variable response to anti-programmed cell death protein 1 (PD-1) therapy, which can be partially explained by a combined positive score (CPS) of tumor and immune cell expression of programmed death-ligand 1 (PD-L1) within the local tumor microenvironment (TME). To better define TME immune determinants associated with treatment efficacy, we conduct a study of n = 48 HNSCC tumors from patients prior to pembrolizumab therapy. Our investigation combines a rapid bioorthogonal multiplex staining method with computational analysis of whole-slide imaging to capture the single-cell spatial heterogeneity and complexity of the TME. Analyzing 6,316 fields of view (FOVs), we provide comprehensive PD-L1 phenotyping and cell proximity assays across the entirety of tissue sections. While none of the PD-L1 metrics adequately predict response, we find that the spatial organization of CCR7 dendritic cells (DCs) in niches better predicts overall patient survival than CPS alone. This study highlights the importance of understanding the spatial context of immune networks for immunotherapy.