ESTRO 2024 - Abstract Book

S5395

Radiobiology - Tumour biology

ESTRO 2024

Seven days after SRS, tumor volumes decreased by around 65% for both dosages relative to control group (20 Gy: control 45.06 ± 12.03 mm³ vs. SRS 6.73 ± 2.37 mm³; 40 Gy: control 34.59 ± 24.99 mm³ vs. SRS 9.90 ± 3.19 mm³). With 20 Gy, tumor response was heterogeneous: some animals maintained tumor control, while most experienced rapid tumor growth starting from d30 after SRS. In contrast, 40 Gy significantly diminished tumor proliferation, ensuring lasting progression-free survival. Based on the imaging results, the 20 Gy cohort was divided into responder vs. non responder. Histological appraisal of proliferating cells revealed a significant decrease of around 80% seven days after 20 Gy SRS in the responding group (control 3460 ± 203.9 Ki67+/mm 2 vs. SRS 719.8 ± 228.2 Ki67+/mm 2 ). No significant increase in apoptosis was identified at this timepoint. Long-term observations indicated steadily decreasing amount of Ki67+ cells and a 4-fold increase in apoptotic cells by day 30 (d7: 168.1 ± 49.42 TUNEL+/ mm 2 vs. d30: 464.4 ± 185.7 TUNEL+/mm 2 ). In contrast, the non-responding cohort revealed higher amount of both, proliferating (1706 ± 425.8 Ki67+/mm 2 ) and apoptotic (826.2 ± 479.5 TUNEL+/mm 2 ) cells compared to responders. Neuroinflammation and immune response were evaluated by quantifying TAM positive nuclei relative to total nuclei. A significant accumulation of TAM was observed seven days after 20 Gy SRS in responding group (control: 9.98 ± 4.09% Iba+ cells vs. SRS: 23.16 ± 4.93% Iba+ cells). This increase persisted up to d30 but diminished in the longterm. In non-responders, TAM levels were the lowest in comparison to the control or responding groups (4.15 ± 3.28% Iba+ cells). When correlating TAM recruitment with tumor volume, an inverse relationship was identified. On d7 post treatment, the tumor volume following 40 Gy irradiation was 50% larger compared to the 20 Gy cohort. However, the initial rise in the 40 Gy group was followed by a pronounced 60% volume reduction by d30, without any intervention in between indicating a pseudoprogression (d30: 3.90 ± 1.48 mm³). Similar to 20 Gy SRS, the 40 Gy cohort showed decreased proliferation (control 2472 ± 528.9 Ki67+/mm 2 vs. SRS 1037 ± 363.6 Ki67+/mm 2 ) without increase in apoptosis (control 250.7 ± 70.95 TUNEL+/ mm 2 vs. SRS 236.2 ± 73.91 TUNEL+/ mm 2 ) seven days after irradiation. The extent of TAM recruitment was high on d7 after SRS (control 12.79 ± 3.23% Iba+ cells/total cells vs. SRS 29.46 ± 4.12% Iba+ cells/total cells) and remained on comparable level in the long-term.

Conclusion:

SRS led to a reduction in tumor volume, as evidenced by both volume development and immune activation. Outcomes differ significantly based on irradiation dose: 20 Gy SRS yielded heterogeneous results, whereas 40 Gy ensured consistent long-term progression-free survival. Histological analysis emphasized this disparity, highlighting decreased proliferation in responders and significant growth in non-responsive tumors after 20 Gy SRS. A pivotal element appears to be the immune response. Notably, there's a clear inverse correlation between tumor volume and TAM recruitment. This early observation has the potential to substantially influence future clinical decisions and treatment strategies. After 40 Gy SRS, initial volume increase followed by a decline hints at potential pseudoprogression. Further comprehensive histological appraisal and FACS analyses for further dissection of SRS immunology are in progress.

Keywords: radiosurgery, immuno-radiobiology, tumor biology

2021

Digital Poster

OXPHOS-dependent radiosensitization of patient-derived organoids from pancreatic adenocarcinoma