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<p>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<sup>Prolif_Tox</sup>). We provide multi-dimensional evidence for tumor antigen-specificity of T<sup>Prolif_Tox</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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

摘要

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.