191P - Senolytic treatment remodels glioblastoma microenvironment

Background

Glioblastoma (GBM), isocitrate dehydrogenase wild-type (IDH-WT), is the most aggressive and invasive form of glioma in adults. This primary brain tumor remains refractory to standard protocols, resulting in a very limited patient survival. GBM is a cold tumor, characterized by a low infiltrative lymphocyte pool and the enhanced expression of immunosuppressive molecules which may explain the failure of immunotherapy. We recently showed that partial removal of malignant senescent cells improved the survival of GBM-bearing mice and remodels the tumor microenvironment (TME) towards a less anti-inflammatory phenotype. Further, we observed an upregulation of genes associated with interferon alpha and gamma, pathways which play key roles in immunity activation and anti-tumor response¹.

Methods

To better understand how senescent cells shape the TME and to test whether senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM, we applied a genetic senolytic (p16-3MR + GCV) to an immunocompetent mesenchymal GBM mouse model in combination or not with immune checkpoint inhibitors (ICI). We analyzed the TME using transcriptomic approaches (bulk RNA sequencing) and the overall survival of mice bearing GBM after treatments.

Results

First, we observed that malignant cells were enriched in genes associated with the antigen-presenting machinery in GBM depleted for senescent cells (p16-3MR+GCV, n=9) compared with controls (WT+GCV, n=5). Second, we found that a combination of senolytic and a cocktail of ICI significantly increases the overall survival of mice bearing GBM compared with mice treated with senolytic and control isotypes.

Conclusions

All together our findings suggest a remodeling of the GBM microenvironment upon senescent cells’ removal, facilitating response to ICI. Further work is needed to understand underlying mechanisms of ICI response in a GBM-context and identify the immune cell types responsible for this survival benefit. ¹ Salam, Saliou et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat. Commun. 14, 1–21 (2023).

Legal entity responsible for the study

The authors.

Funding

Ligue contre le Cancer, Fondation ARC, Siric Curamus.

Disclosure

All authors have declared no conflicts of interest.