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While radiotherapy is a key component in the management of more than 80% of breast cancer,
the dose required to achieve a high probability of tumour control can overlap with the rates of
radiation-induced normal tissue side effects, hindering effective treatment. FLASH-RT, delivered
at ultra-high dose rates, was shown to generate comparable anti-tumour effects compared to
conventional dose rate RT (CONV-RT), but spared healthy tissues from side effects. This novel
technique could offer the potential of dose escalation to treat aggressive tumour subtypes such
as triple negative breast cancer (TNBC).
In the present study, we investigated TNBC responses to FLASH-RT across gene transcription,
immune infiltration, and anti-tumour efficacy. Using subcutaneous and orthotopic 4T1 or
orthotopic MDA-MB-231 murine TNBC models, female mice received single (14 or 20 Gy) or
fractionated (5×5.2 or 10×3 Gy) doses of either CONV-RT (0.2 Gy/s) or FLASH-RT (7.7×10⁶ Gy/s).
Tumour growth was monitored in all models, and 4T1 tumour samples were collected 24 hours,
5 days, and 2 weeks post-irradiation for bulk RNA sequencing, flow cytometry, and histology.
All regimens demonstrated iso-efficacy between FLASH and CONV-RT in delaying tumour growth
and prolonging survival. RNA sequencing revealed that, 24 hours post-irradiation, FLASH-RT
upregulated genes associated with lymphoid cell differentiation, activation, recruitment, and
anti-viral/innate immune responses compared to CONV-RT. However, histology and flow
cytometry analysis showed no differences in immune cell infiltration between modalities. We
hypothesize that FLASH-RT’s enhanced expression of immunoregulatory genes observed 24h
post-irradiation may underlie this discrepancy.
In summary, while FLASH- and CONV-RT are equally effective in delaying tumour growth and
modulating the immune response in murine TNBC, transcriptomic analysis uncovered distinct
immunomodulatory profiles, suggesting nuanced mechanisms that warrant further investigation.
