Longitudinal liquid biopsy identifies an early predictive biomarker of immune checkpoint blockade response in head and neck squamous cell carcinoma

Binbin Wang, Robert Saddawi-Konefka, Lauren M. Clubb, Shiqi Tang, Di Wu, Sumit Mukherjee, Sahil Sahni, Saugato Rahman Dhruba, Xinping Yang, Sumeet Patiyal, Chi-Ping Day, Parth A. Desai, Clint Allen, Kun Wang (), J. Silvio Gutkind () and Eytan Ruppin ()
Additional contact information
Binbin Wang: National Institutes of Health (NIH)
Robert Saddawi-Konefka: UC San Diego School of Medicine
Lauren M. Clubb: UC San Diego
Shiqi Tang: Stanford University
Di Wu: University of Illinois Urbana-Champaign
Sumit Mukherjee: National Institutes of Health (NIH)
Sahil Sahni: National Institutes of Health (NIH)
Saugato Rahman Dhruba: National Institutes of Health (NIH)
Xinping Yang: National Institutes of Health (NIH)
Sumeet Patiyal: National Institutes of Health (NIH)
Chi-Ping Day: National Institutes of Health (NIH)
Parth A. Desai: Fox Chase Cancer Center
Clint Allen: National Institutes of Health (NIH)
Kun Wang: University of Illinois Urbana-Champaign
J. Silvio Gutkind: UC San Diego
Eytan Ruppin: National Institutes of Health (NIH)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Immune checkpoint blockade (ICB) has improved outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but predictive biomarkers remain limited. Here, we use a time-resolved, multi-omic approach in a murine HNSCC model to characterize peripheral immune responses to ICB. Single-cell transcriptomics and T/B cell receptor analyses reveal early on-treatment expansion of effector memory T and B cell repertoires in responders, preceding tumor regression. These dynamic immune features inform a composite transcriptional signature that accurately predicts ICB response in independent human HNSCC cohorts. LiBIO outperforms existing biomarkers and generalizes to melanoma, non-small cell lung cancer, and breast cancer without retraining. These findings suggest that early treatment-induced changes in circulating immune repertoires reflect the host’s capacity to mount an effective antitumor response. This work provides a framework for leveraging transient peripheral immune dynamics to develop non-invasive, high-fidelity biomarkers for response to immunotherapy across cancer types.

Date: 2025
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DOI: 10.1038/s41467-025-63538-4

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