Abstract 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. We showed that in the absence of conventional type 1 dendritic cells (cDC1) juvenile mice that underwent whole-brain irradiation suffered loss of memory and neuron hippocampal dysfunction. 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 cDC1 acquire a tolerogenic phenotype and there is a downregulation in the IF-associated microglia after RT and in the presence of Flt3l. Functional studies showed that the neuroprotective effect of cDC1 is dependent on CD8 T lymphocyte. 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.
Sanz et al. (Fri,) studied this question.