Moderator of 1 Session
Presenter of 1 Presentation
RADIATION-INDUCED IMMUNE RESPONSE IN TUMORS IS DOSE RATE INDEPENDENT
Abstract
Background and Aims
To dissect the immune system’s contribution to the anti-tumor activity upon FLASH and CONV radiotherapy (CONV-RT), we used different tumor models (murine lung adenocarcinoma SV2 and SV2-OVA; head & neck mEERL95; Glioblastoma GL261) transplanted in immunocompetent C57BL6/J mice, adaptive immunodeficient Swiss nude mice, and fully immunodeficient NRG (NOD-Rag1nullIL2rgnull) mice.
Methods
Tumor cells were subcutaneously or orthotopically implanted (n=5-14) and irradiated with the eRT6/Oriatron Linac (PMB-Alcen, Fr). Subcutaneous tumors were irradiated with a single 20Gy or hypo-fractionated 3x8Gy and 2x6Gy doses using FLASH (>2,000Gy/s) or CONV-RT (~0.1-0.2Gy/s). Tumor growth delay was evaluated against unirradiated tumor bearing control mice. Orthotopic SV2-OVA lung tumors were treated with 2x6Gy, tumor growth was followed by μCT imaging and survival was monitored. Immunoprofiling was performed 3, 10 and 21 days post-RT by flow cytometry and immunofluorescence.
Results
Single and hypo-fractionated FLASH and CONV-RT were isoeffective in delaying the growth of subcutaneous tumors regardless of whether the host was immunocompetent, partially or fully immunodeficient. Interestingly, in immunocompetent mice bearing GL261 tumors, 20Gy FLASH and CONV-RT induced a complete response. Re-challenge experiments are ongoing to investigate T-cell memory. In orthotopic SV2-OVA tumors, FLASH and CONV-RT caused equal tumor growth delay, improved survival by 7 days and generated a similar immune profile. Three days post-RT, all immune populations dropped by 75% and slowly recovered at 10 days. Importantly at 21 days when 100% of control animals died, the level of CD3+ T cells was higher in both irradiated groups and correlated with enhanced survival (>90%).
Conclusions
Our results show that the radiation-induced immune response is dose rate independent. This study challenges several proffered hypotheses positing that the FLASH effect is immunologically mediated and suggests that standard radio-immunological strategies will be possible in combination with FLASH-RT.