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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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60827-w |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joseph Zenga |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c2df8fffc851490bbd33029387d75688 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c2df8fffc851490bbd33029387d756882025-08-20T04:01:34ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-60827-wRadiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancerJoseph Zenga0Musaddiq J. Awan1Anne Frei2Jamie Foeckler3Rachel Kuehn4Julia Kasprzak5Becky Massey6Jennifer Bruening7Kenneth Akakpo8Monica Shukla9Stuart J. Wong10Angela J. Mathison11Jaime Wendt Andrae12Bryan Hunt13Andrii Puzyrenko14Victor X. Jin15Abdullah A. Memon16Oscar Villarreal Espinosa17Fanghong Chen18Md Shaheduzzaman19Tyce Kearl20Peiman Hematti21Heather A. Himburg22Department of Otolaryngology, Medical College of WisconsinDepartment of Otolaryngology, Medical College of WisconsinDepartment of Radiation Oncology, Medical College of WisconsinDepartment of Radiation Oncology, Medical College of WisconsinDepartment of Radiation Oncology, Medical College of WisconsinDepartment of Dermatology, Medical College of WisconsinDepartment of Otolaryngology, Medical College of WisconsinDepartment of Otolaryngology, Medical College of WisconsinDepartment of Otolaryngology, Medical College of WisconsinDepartment of Radiation Oncology, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinMedical College of WisconsinMedical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinCancer Center, Medical College of WisconsinDepartment of Otolaryngology, Medical College of WisconsinAbstract 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.https://doi.org/10.1038/s41467-025-60827-w |
| spellingShingle | 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 Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer Nature Communications |
| title | Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer |
| title_full | Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer |
| title_fullStr | Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer |
| title_full_unstemmed | Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer |
| title_short | Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer |
| title_sort | radiation therapy results in preferential tumor antigen specific lymphodepletion in head and neck cancer |
| url | https://doi.org/10.1038/s41467-025-60827-w |
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