S100A proteins show a spatial distribution of inflammation associated with the glioblastoma microenvironment architecture.

Background: Glioblastoma IDH wild type (GBM IDH wt) has a poor prognosis and a strongly associated with inflammatory processes. Inflammatory molecules generate positive feedback with tumor cells fueling tumor growth as well as recruitment of immune cells that promote aggressiveness. Although the role of many inflammatory molecules is well known, there are many macromolecules, such as the S100A proteins, whose role is only now beginning to be established. Methods: Using RNA-seq, bioinformatics tools and a cohort of glioma patients to validate the results, we have analysed the inflammatory processes involved in glioma. Transcriptional profiles were also used to define biological processes of relevance to specific S100A proteins. Finally, we characterized the relevant immune populations with an IHC analysis and transcriptional profiling. Results: We have noted an increased expression of S100A in GBM IDH wt compared to gliomas IDH mutants. This allowed us to analyse the involvement of different members of the family, such as S100A9, A11 and A13 as possible regulators of inflammatory processes in the GBM-IDH wt microenvironment. Thus, we observed that S100A9 is located in hypoxic areas linked to the function of neutrophils, S100A11 is found in vascular areas associated with the function of perivascular pericytes and macrophages, and finally, S100A13 which is related to the dysfunction of microglia. Conclusion: Our findings define different functions for S100A9, A11 and A13 proteins that are associated with the architecture of the glioblastoma microenvironment and define its progression. Moreover, these alterations can be reversed by the RAGE inhibitor, Azeliragon which is in a phase I/II clinical trial NCT05635734.