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

  • Cancer Immunol Res. 2025 Jul 2;13(7):1022-1036. doi: 10.1158/2326-6066.CIR-24-0807.
Berta Segura-Collar  #  1  2 ,  Blanca Cómitre-Mariano  #  1  2 ,  Denisse Alcivar López  1  2 ,  Lucia Modejar-Ruescas  1  2 ,  Marta Caamaño-Moreno  1  2 ,  Elena Tovar Ambel  3 ,  Javier Gutierrez-Martin  4 ,  Marina Garín  4 ,  Oscar Toldos  1  2 ,  Aurelio Hernández-Laín  1  2 ,  Ricardo Gargini  1  2 ,  Juan M Sepúlveda  1  5
Affiliations
  • 1. Instituto de Investigación Biomédicas I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 2. Pathology and Neurooncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 3. Biochemistry and Molecular Biology Department, School of Biology, Complutense University, Madrid, Spain.
  • 4. Division of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
  • 5. Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • # Contributed equally.
PMID: 40208240 DOI: 10.1158/2326-6066.CIR-24-0807
Abstract

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.

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