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Translational Therapeutics

Association of DNA damage response signals and oxidative stress status with nivolumab efficacy in patients with Head and Neck Squamous Cell Carcinoma

British Journal of Cancer volume 133, pages 353–364 (2025)Cite this article

Subjects

Abstract

Background

Accumulating evidence suggests that deregulation of DNA damage response (DDR) network affects multiple aspects of the immune system. Herein, we tested the hypothesis that DDR-related signals, measured in peripheral blood mononuclear cells (PBMCs) from Head and Neck Squamous Cell Carcinoma (HNSCC) patients, correlate with the response to immune checkpoint inhibitors.

Methods

Oxidative stress and DDR-related signals were evaluated in PBMCs from 26 healthy controls and 50 recurrent/metastatic HNSCC patients at baseline, who participated in a phase II nivolumab trial (NCT03652142). Spatial transcriptomics in three molecularly defined tissue compartments (tumour, leucocyte, macrophage) from biopsies of overlapping cases were also investigated.

Results

PBMCs from responders to nivolumab therapy showed significantly lower oxidative stress, endogenous DNA damage, DNA repair capacities and apoptosis rates compared with non-responders (all P < 0.04). The analysis of tissue RNA in situ data illustrated that DNA repair pathways showed enrichment in the macrophage compartment of baseline tissue biopsies of responders compared with non-responders (P = 0.049).

Conclusions

Our findings demonstrate that oxidative stress and deregulated DDR-related signals measured in PBMCs from HNSCC patients at baseline correlate with response to nivolumab and, if further validated, may be exploited as novel non-invasive biomarkers and the design of clinical trials.

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Fig. 1: Endogenous DNA damage and response to nivolumab therapy.
Fig. 2: Oxidative stress and response to nivolumab therapy.
Fig. 3: Individual NER capacity and response to nivolumab therapy.
Fig. 4: Individual DSB repair capacity and response to nivolumab therapy.
Fig. 5: Gene expression profile of tissue biopsies.

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Data availability

All data relevant to the study are included in the article or uploaded as supplementary information.

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Acknowledgements

Graphical abstract contains items that have been adapted from Servier Medical Art by Servier (https://smart.servier.com), licensed under Creative Commons Attribution 4.0 International License.

Funding

This work was supported from the Hellenic Society of Medical Oncology (HeSMO).

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Author notes

  1. These authors contributed equally: Christina Papanikolaou, Panagiota Economopoulou.

Authors and Affiliations

  1. Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece

    Christina Papanikolaou & Vassilis L. Souliotis

  2. Oncology Unit, 2nd Department of Internal Medicine, Attikon University Hospital, Athens, Greece

    Christina Papanikolaou, Panagiota Economopoulou, Ioannis Kotsantis, Niki Gavrielatou, Maria Anastasiou, Myrto Moutafi, Anastasios Kyriazoglou, George-Romanos P. Foukas, Ioannis M. Lelegiannis & Amanda Psyrri

  3. Second Department of Pathology, Attikon University Hospital, Athens, Greece

    Aris Spathis, Ioannis Panayiotides & Periklis Foukas

  4. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    Niki Gavrielatou & David Rimm

  5. Department of Oncology, CHUV - Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Periklis Foukas

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Contributions

Conceptualisation: AP, VLS, CP. Methodology: CP, PE, AS, IK, MA, NG, PF, IP, GPF, DR, IL. Investigation: AP, VLS, CP, PE, PF, MM. Visualisation: PE, IK, MA, IL, IP. Resources: AP, PE, DR, MM, AK. Funding acquisition: AP, VLS. Writing original draft: CP, PE. Writing and approval: all authors.

Corresponding author

Correspondence to Amanda Psyrri.

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Competing interests

Amanda Psyrri has received honoraria and research funding from BMS, MSD, Roche, Pfizer, Merck Serono. AstraZeneca, Ipsen. She has also received research support from KURA Oncology.

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The study was approved by the Ethical Committee of Attikon Hospital, Athens, Greece. All participants gave informed consent to participate in the study. The study was conducted according to the Declaration of Helsinki.

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Papanikolaou, C., Economopoulou, P., Spathis, A. et al. Association of DNA damage response signals and oxidative stress status with nivolumab efficacy in patients with Head and Neck Squamous Cell Carcinoma. Br J Cancer 133, 353–364 (2025). https://doi.org/10.1038/s41416-025-03032-2

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