What question did this study set out to answer?

The study aims to explore immune and genomic factors that correlate with disease-free survival in patients receiving pembrolizumab alongside chemoradiotherapy for high-risk HNSCC.

June 27, 2026

Tumoral and Systemic Immune Correlates of Response to Concurrent Pembrolizumab and Chemoradiotherapy in Patients with Resected High-Risk Head and Neck Squamous Cell Carcinoma

Key Points

The study aims to explore immune and genomic factors that correlate with disease-free survival in patients receiving pembrolizumab alongside chemoradiotherapy for high-risk HNSCC.
Phase I trial with 34 patients receiving adjuvant pembrolizumab with CRT.
Assessment of PD-L1 expression via combined positive score and spatial imaging.
Analysis of TP53 mutations through whole-exome sequencing and evaluation of circulating immune subsets.
Patients with PD-L1 CPS≥20 had numerically lower disease-free survival (DFS) than those with CPS<20.
Elevated serum arginase-1 correlated with inferior DFS, while higher GM-CSF, IL-2, and nectin-2 levels associated with better outcomes.
Higher frequencies of CD8+ granzyme K+ T cells and increased effector T cell populations linked to improved DFS.

Abstract

PURPOSE: Patients with pathologically high-risk, HPV-negative HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). As CRT can upregulate PD-1/L1 immune checkpoints, adding pembrolizumab may reverse treatment-induced immunosuppression. NRG-HN003 was a phase I trial assessing the safety and recommended phase II schedule of adjuvant pembrolizumab with CRT. Here, we report exploratory immune and genomic correlates of disease-free survival (DFS). PATIENTS AND METHODS: Thirty-four patients received pembrolizumab with CRT. PD-L1 expression was quantified by combined positive score (CPS) and spatial localization of PD-L1+ cells was assessed by multispectral imaging of baseline tumors. Disruptive TP53 mutations were evaluated by whole-exome sequencing. Soluble serum biomarkers were evaluated by Luminex, and circulating immune subsets were profiled by spectral flow cytometry at baseline and post-treatment. RESULTS: Patients with PD-L1 CPS≥20 showed numerically lower DFS than those with CPS<20; however, higher densities of PD-L1+ stromal cells were associated with more favorable outcomes. Disruptive TP53 mutations were not a significant negative prognostic factor. Among soluble markers at baseline, elevated serum arginase-1 was associated with inferior DFS, while higher levels of GM-CSF, IL-2 and nectin-2 were associated with more favorable outcomes. In circulating immune cells, higher baseline frequencies of CD8+ granzyme K+ T cells, as well as higher post-treatment frequencies of CD8+ CD39+ and regulatory CD4+ T cells, were associated with improved DFS. Increased effector and central memory T cell populations, especially post-treatment, also showed favorable associations with DFS. CONCLUSIONS: These findings highlight multiple potential immunologic correlates of pembrolizumab with CRT in high-risk HNSCC, supporting further evaluation and validation in larger, adequately powered trials.

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