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

Authors

Lazar Vujanovic, Pedro Torres-Saavedra, Fei Tu, Ravindra Uppaluri, Min Yao, Josephine Chen, Richard Jordan, Jessica L Geiger, Srinivas Jujjavarapu, Arnab Chakravarti, Minh Phan, Farzan Siddiqui, Aditi Kulkarni, Pragati Upadhyay, Brian Robert Isett, Gabriel L Sica, Carly Reeder, Riyue Bao, Jie Chen, Marion Joy, Tanner Freeman, Jonathan Harris, Quynh-Thu Le, Julie E Bauman, Robert L Ferris

Published in

Clinical cancer research : an official journal of the American Association for Cancer Research. Jun 25, 2026. Epub Jun 25, 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.

PMID:
42347893
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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