Ultrahigh-Dose-Rate Radiation Therapy Spares Lymphocytes and Increases T cell Infiltration in Human Papillomavirus–Positive Tumors

@article{saenz2026ultrahighdoserate,
  title = {{Ultrahigh-Dose-Rate Radiation Therapy Spares Lymphocytes and Increases T cell Infiltration in Human Papillomavirus–Positive Tumors}},
  author = {Francisco Sáenz and Brett Velasquez and Trey Waldrop and Edgardo A Aguilar and Kathryn R. Cox and Abagail M. Delahoussaye and Caddie Laberiano-Fernández and Letícia Campos Clemente and Luke Connell and Nefetiti Mims and Denae W. Neill and Edwin R. Parra and Karen Clise-Dwyer and Emil Schüler and Michael T. Spiotto},
  journal = {Advances in Radiation Oncology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.adro.2026.102138},
  url = {https://doi.org/10.1016/j.adro.2026.102138},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Ultrahigh-Dose-Rate Radiation Therapy Spares Lymphocytes and Increases T cell Infiltration in Human Papillomavirus–Positive Tumors
AU  - Francisco Sáenz
AU  - Brett Velasquez
AU  - Trey Waldrop
AU  - Edgardo A Aguilar
AU  - Kathryn R. Cox
AU  - Abagail M. Delahoussaye
AU  - Caddie Laberiano-Fernández
AU  - Letícia Campos Clemente
AU  - Luke Connell
AU  - Nefetiti Mims
AU  - Denae W. Neill
AU  - Edwin R. Parra
AU  - Karen Clise-Dwyer
AU  - Emil Schüler
AU  - Michael T. Spiotto
PY  - 2026
DA  - 2026/10/01
JO  - Advances in Radiation Oncology
DO  - 10.1016/j.adro.2026.102138
UR  - https://doi.org/10.1016/j.adro.2026.102138
AB  - Radiotherapy (RT) delivered at conventional dose rates (CONV) can both stimulate antitumor immune responses and inhibit these immune responses by depleting circulating lymphocytes. Given the observed normal tissue sparing associated with ultra-high dose rate (FLASH) RT, we hypothesized that FLASH RT may protect lymphocytes while increasing the immunogenicity of cancer cells. We irradiated cancer cell lines in vitro with FLASH RT or CONV RT and assessed immunogenic mRNA and protein expression. Both HPV-positive cell lines MEER and TC-1 showed upregulation of Calr, Hmgb1 , and cGAS-STING family members after FLASH RT but not after CONV RT in vitro . To assess changes in lymphocyte populations, we irradiated murine mEER tumors in syngeneic C57BL/6 mice with 27 Gy in 3 fractions of FLASH RT or CONV RT. In mice bearing FLASH irradiated tumors, tumor-draining lymph nodes contained greater numbers of CD8 + T cells (FLASH 1.7×10 4 vs 0.8×10 4 CONV; P <0.001) and CD4 + T cells (FLASH 2.3×10 4 vs CONV 1.2×10 4 ; P <0.001) after irradiation. FLASH RT was associated with increased numbers of activated CD44 + CD62L lo CD8 + and CD4 + lymphocytes. In irradiated tumors, FLASH RT was associated with increased CD8 + tumor-infiltrating lymphocytes, increased PD1 expression on these lymphocytes and increased PDL1 expression on macrophages. Compared with CONV RT, FLASH RT spared activated T cells in tumor-draining lymph nodes and in tumors but increased checkpoint inhibitor expression in tumors. These results suggest that FLASH RT may enhance antitumor immune responses by maintaining the immunogenic effects of RT while preserving lymphocyte numbers, which may be augmented with immune checkpoint blockade. Significance Radiation-induced lymphopenia is associated with poorer survival outcomes. New treatment approaches, like FLASH radiation therapy (FLASH RT), which reduce lymphopenia and enhance the antitumor response, could potentially lead to better outcomes for cancer patients.
SN  - 2452-1094
ER  -