P06.11.A CONVENTIONAL TYPE 1 DENDRITIC CELLS ENHANCE NEUROPROTECTION IN PEDIATRIC BRAIN TUMOR RADIOTHERAPY

Abstract BACKGROUND As of today, many of the pediatric brain tumor treatment regimens include radiotherapy (RT). Despite protocol improvements, brain irradiation leads to adverse effects on cognitive function, such as problems with learning, memory, and mood disorders in long-term survivors. Thus, strategies geared to improve the quality of life for these children while maintaining efficacy are of the utmost interest. Neuroinflammation, specifically reactive microglia, has been postulated as one of the leading causes of cognitive decline after RT. However, it remains unclear to what extent other non-brain resident immune cells play a role in such neurotoxicity. Dendritic cells, the main antigen presenting cells, can modulate innate and adaptive immunity, becoming a promising target for neuroinflammation prevention. MATERIAL AND METHODS Juvenile mice were subjected to whole-brain irradiation (WBI) with 10Gy evaluating cognitive performance via behavioral test (NOR and MWM) 30/90/180 days upon RT, in the presence or abscence (Batf3ko strain) of cDC1. The therapeutical benefit of cDC1 was evaluated by in vivo expansion with Flt3l in a medulloblastoma mice model treated with locoregional radiotherapy. RESULTS We showed that in the absence of conventional type 1 dendritic cells (cDC1), juvenile mice that underwent WBI suffered increased memory loss and neuron hippocampal dysfunction. Interestingly, the blockade of Clec9a (cDC1 specific dead sensor) exacerbates cognitive dysfunction and promotes reactive microglia and neurotoxic astrocytes. Of relevance, in vivo expansion of cDC1 by systemic administration of Flt3l prevents neurocognitive sequelae without interfering with the anti-tumor effect of local RT in medulloblastoma-bearing mice. Single -cell analysis revealed that Flt3l treatment conditions microglia phenotype into an anti-inflammatory signature. Functional studies showed that the neuroprotective effect of cDC1 is dependent on CD8 T lymphocytes, which preserves from the sequelae of a second irradiation. CONCLUSION In summary, we demonstrated that cDC1 play an indispensable role in preventing RT-associated cognitive decline and neurotoxicity. These encouraging results provide a strong rationale for exploiting cDC1 expansion as a neo-adjuvant in pediatric brain tumor patients who are subjected to radiotherapy.