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

Tumoral and Systemic Immune Correlates of Response to Concurrent Pembrolizumab and Chemoradiotherapy in Patients with Resected High-Risk Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Vujanovic, L., Torres-Saavedra, P., Tu, F., Uppaluri, R., Yao, M., Chen, J., Jordan, R., Geiger, J. L., Jujjavarapu, S., Chakravarti, A., Phan, M., Siddiqui, F., Kulkarni, A., Upadhyay, P., Isett, B. R., Sica, G. L., Reeder, C., Bao, R., Chen, J., Joy, M., Freeman, T., Harris, J., Le, Q. T., Bauman, J. E., Ferris, R. L. 2026

Abstract

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).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.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.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.

View details for DOI 10.1158/1078-0432.CCR-25-4796

View details for PubMedID 42347893