Abstract Pediatric low-grade gliomas (pLGG), the most common brain tumors in children, remain a significant cause of morbidity. Therefore, novel therapeutic strategies are urgently needed. Although some studies have characterized the tumor microenvironment (TME) of pLGG using bulk and/or single-cell RNA sequencing, little is known about the spatial proteomic architecture of pLGG and its relationship to clinico-molecular features. Our study utilized imaging mass cytometry and a panel of 28 metal-labeled antibodies to unravel the spatial organization of 120 primary pLGG samples from the LOGGIC Core BioClinical DataBank. Cellular neighborhood analysis mapped the spatial organization of pLGG TME and several clinical features (entity, tumor location, disease progression status, age and sex) were used to measure their putative association with the enrichment of key cell populations and structures. Here, we revealed myeloid cells - comprising resident microglia and diverse bone marrow-derived macrophages - as the predominant immune population in the TME, notably in optic pathway tumors, alongside limited T-lymphoid infiltrates. Importantly, we identified an immunophenotype signature based on the presence of myeloid cell populations that was significantly associated with disease progression in our cohort. Clinically, the myeloid cell populations, together with an increased expression of the immune checkpoint protein TIM-3, suggest the presence of an immunosuppressive environment. Notably, p-ERK positivity was high in the myeloid populations, indicating a possible link between TIM-3 and MAPK activity in myeloid cells. Spatial analysis unveiled intriguing cell interactions, including noteworthy myeloid interactions, and specific cellular neighborhoods consistently associated with progression-free survival (PFS) in all patients, and particularly those at risk of progression. Our study, the largest on pLGG TME to date, highlights the immunosuppressive role of diverse myeloid infiltrates and suggests combining TIM-3 with MAPK inhibition as a promising therapeutic strategy targeting both the TME and oncogenic MAPK activation in these debilitating tumors.
Andrade et al. (Fri,) studied this question.