The TRIB2–DNMT1 pathway generates an immune cold microenvironment in glioblastoma and its inhibition promotes immunotherapy

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.