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Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer
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Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer
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Journal Article
Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer
2025
Overview
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 (T
Prolif_Tox
). We provide multi-dimensional evidence for tumor antigen-specificity of T
Prolif_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.
Combining radiation therapy (RT) with immunotherapy has had limited therapeutic benefits in the treatment of head and neck cancer (HNSCC). Here, the authors present a multi-omics analysis of patient biopsies pre- and post- hypofractionated RT and uncover RT-mediated depletion of tumor-reactive CD8+ T cells as the underlying cause of immunologic radioresistance in HNSCC.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/51
/ 45/91
/ Aged
/ Antigens
/ Antigens, Neoplasm - immunology
/ Biopsy
/ Cancer
/ Female
/ Head and Neck Neoplasms - immunology
/ Head and Neck Neoplasms - pathology
/ Head and Neck Neoplasms - radiotherapy
/ Humanities and Social Sciences
/ Humans
/ Immune checkpoint inhibitors
/ Lymphocytes, Tumor-Infiltrating - immunology
/ Lymphocytes, Tumor-Infiltrating - radiation effects
/ Male
/ Patients
/ Science
/ Squamous Cell Carcinoma of Head and Neck - immunology
/ Squamous Cell Carcinoma of Head and Neck - pathology
/ Squamous Cell Carcinoma of Head and Neck - radiotherapy
/ Tumor Microenvironment - immunology
/ Tumor Microenvironment - radiation effects
/ Tumor-infiltrating lymphocytes
/ Tumors
