Biology subjects

Delahoussaye, A.

Publications and source records attributed to Delahoussaye, A..

2 recordsLinked to original sources

bioRxiv2025

FLASH radiotherapy spares lymphocytes in tumor-draining lymph nodes and increases infiltration of immune cells in tumors

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 1.7x104 vs 0.8x104 CONV; P<0.001) and CD4+ T cells (FLASH 2.3x104 vs CONV 1.2x104; P<0.001) after irradiation. FLASH RT was associated with increased numbers of activated CD44+CD62LloCD8+ 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. SignificanceRadiation-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.

cancer biology↗

bioRxiv2024

Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract

BackgroundThe understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. PurposeWe sought to evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP). MethodsC57BL/6J mice were subjected to total abdominal irradiation (11-14 Gy single fraction) under conventional irradiation (low DPP and low MDR, CONV) and various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. The effects of DPP were evaluated for DPPs of 1-6 Gy while the total dose and MDR were kept constant; the effects of MDR were evaluated for the range 0.3- 1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay. ResultsWithin each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to better sparing of regenerating crypts, with a more prominent effect seen at 12 and 14 Gy TAI. However, at fixed DPPs >4 Gy, similar sparing of crypts was demonstrated irrespective of MDR (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV for all MDRs from 0.3 Gy/s to 104 Gy/s, but at a lower DPP of 0.93 Gy, increasing MDR produced a greater survival effect. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model. ConclusionsThis study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.

cancer biology↗