2026-06-29T02:51:32Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1252042025-10-21T15:46:53Zcom_20.500.14352_14col_20.500.14352_15

The TRIB2–DNMT1 Pathway Generates an Immune-Cold Microenvironment in Glioblastoma, and Its Inhibition Promotes Immunotherapy Segura-Collar, Berta Cómitre-Mariano, Blanca López, Denisse Alcivar Modejar-Ruescas, Lucia Caamaño-Moreno, Marta Tovar Ambel, Elena Gutiérrez-Martín, Javier Garín, Marina Toldos González, Óscar Hernández Laín, Aurelio Gargini, Ricardo Sepúlveda, Juan M. 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. 2025-10-21T15:46:53Z 2025-10-21T15:46:53Z 2025-10-21T15:46:53Z 2025-07-02 journal article https://hdl.handle.net/20.500.14352/125204 2326-6066 10.1158/2326-6066.cir-24-0807 2326-6074 eng 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 metadata only access American Association for Cancer Research (AACR)