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

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

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...

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Main Authors: 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, Heather A. Himburg
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60827-w
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Summary: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.
ISSN:2041-1723

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