Abstract IA016: Mapping microglia – tumor crosstalk in pediatric brain cancer

Abstract The management of diffuse midline gliomas (DMG) is one of the greatest challenges in the field of pediatric oncology. Available treatments do not improve the poor survival rates, and preclinical research is struggling to find new targets that could have the potential to revolutionize the therapeutic approach. In most of the current preclinical tools, microglia and macrophages are not taken into account, despite being the most abundant immune players in the brain tumor microenvironment. To address this issue, we established neural organoids and macrophages (iMacs) from induced pluripotent stem cells (iPSC) derived from pediatric patients treated for DMG ("autologous immuno-organoids"). We have reprogrammed fibroblasts into iPSC from 9 children with DMG and generated autologous immuno-organoids for 4 of them. These "avatars" provide a unique preclinical model to which tumor cells from the same patient can be added, enabling us to better understand the crosstalk between the tumor and its immunological microenvironment, and to evaluate new immunotherapies. In particular, we show here that iMacs decrease tumor proliferation and tumor cell-invasion capability in neural organoids, with such effect reduced upon iMac depletion using CSF1R inhibitor treatment. Genes/signaling pathways identified by multi-omics analysis and validated at proteomic level show a reciprocal reprogramming of tumor cells and iMacs over time. Altogther, our approach reveals an unique tumor macrophage crosstalk that will be targeted by tailored immunotherapies or gene modification to validate their impact on tumor progression. Citation Format: Florent Ginhoux, Claudia Pasqualini. Mapping microglia – tumor crosstalk in pediatric brain cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA016.