Inflammation and limited adaptive immunity predict worse outcomes on immunotherapy in head and neck cancer
Most patients with relapsed or metastatic head and neck squamous cell carcinoma (rmHNSCC) do not experience durable responses to PD-1 immune checkpoint inhibitors. PD-L1 tissue expression is the most commonly assessed response marker, but an insufficient predictor of treatment outcome. To identify suitable response biomarkers, we profiled the FOCUS trial (Registered at ClinicalTrials.gov: NCT05075122) cohort for several blood- and tissue-based markers. PD-L1 levels in the tumor or tumor microenvironment were not associated with treatment benefit. In contrast, inflammation-related markers such as IL-6, sCD25, and sTIM-3, as well as high peripheral neutrophils, cell-free DNA levels, and T cell receptor repertoire clonality, were associated with poor clinical outcomes. Patients lacking these high-risk markers performed remarkably well on inhibition of immune checkpoints with pembrolizumab. Biomarker-guided patient selection for pembrolizumab monotherapy or novel combinatorial approaches-potentially including anti-inflammatory agents-for patients with immune-impaired, inflammatory profiles may be the next step in personalizing immunotherapy for these hard-to-treat patients.
Authors
- Paul Schmidt-Barbo (ORCID: https://orcid.org/0009-0008-0871-7555)
- Lisa Paschold (ORCID: https://orcid.org/0000-0003-0020-1315)
- Christoph Schultheiß (ORCID: https://orcid.org/0000-0001-9789-5776)
- Ingunn Westgaard
- Philippe Schafhausen
- Anna Brandt (ORCID: https://orcid.org/0009-0000-7390-1692)
- D Hahn
- Mascha Binder (ORCID: https://orcid.org/0000-0003-0663-3004)
- Mareike Tometten
- Simone Kowoll
- Konrad Klinghammer (ORCID: https://orcid.org/0000-0001-6425-4833)
- Axel Hinke (ORCID: https://orcid.org/0000-0002-6037-8836)
- Alexander Stein (ORCID: https://orcid.org/0000-0002-9768-0086)
- Markus Blaurock (ORCID: https://orcid.org/0000-0001-6442-1283)
Institutions
- Universität Hamburg (DE)
- Universitätsmedizin Greifswald (DE)
- Eppendorf (Germany) (DE)
- University Hospital of Basel (CH)
- Humboldt-Universität zu Berlin (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Ultimovacs (Norway) (NO)
- Klinikum Stuttgart (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- RWTH Aachen University (DE)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s41698-025-01020-6
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- National Science Foundation
- Universitätsspital Basel
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung