Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer

Joseph Zenga (), Musaddiq J. Awan, Anne Frei, Jamie Foeckler, Rachel Kuehn, Julia Kasprzak, Becky Massey, Jennifer Bruening, Kenneth Akakpo, Monica Shukla, Stuart J. Wong, Angela J. Mathison, Jaime Wendt Andrae, Bryan Hunt, Andrii Puzyrenko, Victor X. Jin, Abdullah A. Memon, Oscar Villarreal Espinosa, Fanghong Chen, Md Shaheduzzaman, Tyce Kearl, Peiman Hematti and Heather A. Himburg ()
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Joseph Zenga: Medical College of Wisconsin
Musaddiq J. Awan: Medical College of Wisconsin
Anne Frei: Medical College of Wisconsin
Jamie Foeckler: Medical College of Wisconsin
Rachel Kuehn: Medical College of Wisconsin
Julia Kasprzak: Medical College of Wisconsin
Becky Massey: Medical College of Wisconsin
Jennifer Bruening: Medical College of Wisconsin
Kenneth Akakpo: Medical College of Wisconsin
Monica Shukla: Medical College of Wisconsin
Stuart J. Wong: Medical College of Wisconsin
Angela J. Mathison: Medical College of Wisconsin
Jaime Wendt Andrae: Medical College of Wisconsin
Bryan Hunt: Medical College of Wisconsin
Andrii Puzyrenko: Medical College of Wisconsin
Victor X. Jin: Medical College of Wisconsin
Abdullah A. Memon: Medical College of Wisconsin
Oscar Villarreal Espinosa: Medical College of Wisconsin
Fanghong Chen: Medical College of Wisconsin
Md Shaheduzzaman: Medical College of Wisconsin
Tyce Kearl: Medical College of Wisconsin
Peiman Hematti: Medical College of Wisconsin
Heather A. Himburg: Medical College of Wisconsin

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (TProlif_Tox). We provide multi-dimensional evidence for tumor antigen-specificity of TProlif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC.

Date: 2025
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DOI: 10.1038/s41467-025-60827-w

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