RT Journal Article
T1 The TRIB2–DNMT1 Pathway Generates an Immune-Cold Microenvironment in Glioblastoma, and Its Inhibition Promotes Immunotherapy
A1 Segura-Collar, Berta
A1 Cómitre-Mariano, Blanca
A1 López, Denisse Alcivar
A1 Modejar-Ruescas, Lucia
A1 Caamaño-Moreno, Marta
A1 Tovar Ambel, Elena
A1 Gutiérrez-Martín, Javier
A1 Garín, Marina
A1 Toldos González, Óscar
A1 Hernández Laín, Aurelio
A1 Gargini, Ricardo
A1 Sepúlveda, Juan M.
AB 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.
PB American Association for Cancer Research (AACR)
SN 2326-6066
YR 2025
FD 2025-07-02
LK https://hdl.handle.net/20.500.14352/125204
UL https://hdl.handle.net/20.500.14352/125204
LA eng
NO Segura-Collar B, Cómitre-Mariano B, Alcivar López D, Mondéjar-Ruescas L, Caamaño-Moreno M, Tovar Ambel E, Gutiérrez-Martín J, Garín M, Toldos Ó, Hernández-Laín A, Gargini R, Sepúlveda JM. (2025). The TRIB2–DNMT1 Pathway Generates an Immune-Cold Microenvironment in Glioblastoma, and Its Inhibition Promotes Immunotherapy. Cancer Immunol Res, 13(7):1022–1036. https://doi.org/10.1158/2326-6066.CIR-24-0807
NO Study conducted at Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, and CIEMAT. Equal contribution by Berta Segura-Collar and Blanca Cómitre-Mariano.
NO Instituto de Salud Carlos III
NO CIEMAT
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 24 mar 2026