Cancer Immunol Res. 2025 Apr 10. doi: 10.1158/2326-6066.CIR-24-0807. Online ahead of print.
ABSTRACT
The lack of response of glioblastoma (GBM) to immunotherapy is closely related to the limited number of T cells in the tumor microenvironment (TME). However, it is still not known why GBM is characterized by an immune-cold TME with reduced CD8+ T-cell infiltration when there is substantial myeloid cell infiltration and a substantial alteration of the blood-brain barrier. The aim of this study was to identify regulators of low CD8+ T-cell infiltration in GBM. Using transcriptomic screening, we found that TRIB2 is a regulator of the immune-cold microenvironment characteristic of GBM. Further analysis of a cohort of 114 brain tumors with immunohistochemistry, RNA-sequencing and quantitative real-time PCR, showed that TRIB2 inhibited the transcription of genes involved in antigen presentation by the tumor cells and of genes involved in T-cell recruitment by modulating expression of methylation regulators, in particular DNMT1. Further, we observed 75% survival after TRIB2 inhibition in murine glioma models and showed transcriptomic reprogramming by Decitabine of genes involved in the processes described above. In our patient-derived tumor fragments assay we observed a consistent generalized response to decitabine, suggesting that DNMT1 inhibition could be a promising therapeutic strategy for GBM.
PMID:40208240 | DOI:10.1158/2326-6066.CIR-24-0807