SMAC mimetic drives microglia phenotype and glioblastoma immune microenvironment.

Published in: Cell Death Dis 2024 Sep; 15(9): 676

Authors: Snacel-Fazy E, Soubéran A, Grange M, Joseph K, Colin C, Morando P, Luche H, Pagano A, Brustlein S, Debarbieux F, Toutain S, Siret C, van de Pavert SA, Rougon G, Figarella-Branger D, Ravi VM, Tabouret E, Tchoghandjian A

Summary

Tumor-associated macrophages/microglia (TAMs) are highly plastic and heterogeneous immune cells that can be immune-supportive or tumor-supportive depending of the microenvironment. TAMs are the most abundant immune cells in glioblastoma (GB), and play a key role in immunosuppression. Therefore, TAMs reprogramming toward immune-supportive cells is a promising strategy to overcome immunosuppression. By leveraging scRNAseq human GB databases, we identified that Inhibitor of Apoptosis Proteins (IAP) were expressed by TAMs. To investigate their role in TAMs-related immunosuppression, we antagonized IAP using the central nervous system permeant SMAC mimetic GDC-0152 (SMg). On explants and cultured immune cells isolated from human GB samples, SMg modified TAMs activity. We showed that SMg treatment promoted microglia pro-apoptotic and anti-tumoral function via caspase-3 pro-inflammatory cleavage and the inhibition of tumoroids growth. Then we designed a relevant immunogenic mouse GB model to decipher the spatio-temporal densities, distribution, phenotypes and function of TAMs with or without SMg treatment. We used 3D imaging techniques, a transgenic mouse with fluorescent TAM subsets and mass cytometry. We confirmed that SMg promoted microglia activation, antigen-presenting function and tumor infiltration. In addition, we observed a remodeling of blood vessels, a decrease in anti-inflammatory macrophages and an increased level of monocytes and their mo-DC progeny. This remodeling of the TAM landscape is associated with an increase in CD8 T cell density and activation. Altogether, these results demonstrated that SMg drives the immunosuppressive basal microglia toward an active phenotype with pro-apoptotic and anti-tumoral function and modifies the GB immune landscape. This identifies IAP as targets of choice for a potential mechanism-based therapeutic strategy and SMg as a promising molecule for this application.

Link to Pubmed [PMID] – 39278921

Link to HAL – hal-04767023

Link to DOI – 10.1038/s41419-024-07056-z