The TRIB2–DNMT1 Pathway Generates an Immune-Cold Microenvironment in Glioblastoma, and Its Inhibition Promotes Immunotherapy

The lack of response of glioblastoma (GBM) to immunotherapy is closely related to the limited number of T cells in the tumor microenvironment. However, it is still not known why GBM is characterized by an immune-cold tumor microenvironment 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 tribbles homolog 2 (TRIB2) is a regulator of the immune-cold microenvironment characteristic of GBM. Further analysis of a cohort of 114 brain tumors with IHC, RNA sequencing, and qRT-PCR showed that TRIB2 inhibited the transcription of genes involved in antigen presentation by the tumor cells and those involved in T-cell recruitment by modulating the expression of methylation regulators, in particular DNA methyltransferase 1. 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 DNA methyltransferase 1 inhibition (DNMT1) could be a promising therapeutic strategy for GBM.