Projects

Immunomodulation of the tumor microenvironment for the treatment of diffuse midline glioma

At the meeting of the Board of Trustees held on December 22, 2021, the allocation of the 2021 Aid from the Blanca Morell Ariza Foundation for a period of 3 years and a total budget of €195,000 was ratified for Research on Diffuse Midline Gliomas proposed by Sara Labiano from the University Clinic of Navarra under the title “Immunomodulation of the tumor microenvironment for the treatment of diffuse midline glioma”. The proposal was selected by the Scientific Committee in accordance with the call published on September 1, taking into account criteria of : Scientific-technical quality, capacity of the research team, potential impact of transfer to clinical practice, dissemination and budget.

Diffuse midline gliomas (DMG) appear mainly in children and adolescents, constituting, with a 5-year survival of less than 1%, the main cause of non-accidental infant death. Despite advances in current treatments, the prognosis for patients with GDM remains very poor. Although in the last decade our knowledge about its genomic and epigenomic characteristics has experienced unprecedented progress, this advance has not led to significant improvements in therapy despite more than two hundred clinical trials. All this emphasizes the need for effective treatments for this disease. It has been shown that the immune system plays a very relevant role in the antitumor response, not only in immunotherapy but also in conventional therapies such as radiotherapy or chemotherapy. The immunological panorama of these tumors is currently being studied. Recent publications have preliminarily shown that the tumor microenvironment of patients with DIPG (a type of GDM in the brainstem) is made up of a myeloid immune majority and lacks cytotoxic lymphocytes (TILs). In fact, the absence of TILs could be the main cause of the failure of antibodies blocking the so-called checkpoints (such as PD1 or PDL1) in pediatric brain tumors in the clinic. For this reason, we firmly believe that the study of majority immune populations such as microglia (resident macrophages of the brain), tumor-infiltrating macrophages or dendritic cells will help to find new candidate genes against which to develop drugs for the treatment of this disease and that also help recruit T lymphocytes to generate a powerful anti-tumor response. Therefore, one of the main objectives of this project is the characterization of the immune microenvironment of these tumors, an emerging field in the context of pediatric brain tumors. To do this, we will use state-of-the-art technologies such as single cell RNAseq and spatial transcriptomics in tumor tissue samples from both patient biopsies and orthotopic mouse models that recapitulate the genetic context of said patients. We will obtain these samples at different tumor stages and from different locations in the midline (brain stem, thalamus or spinal cord) to cover extensively the different GDM scenarios that we find in reality. On the other hand, in line with what has been reported in glioblastoma, we have detected that the blockade of TIM3, a negative regulator of immune responses in the tumor, improves survival in models of DIPG mediated by the innate immune system (microglia and macrophages) and adaptive (dendritic and T lymphocytes). For this reason, we would like to verify the efficacy of this therapy in GDMs in other locations such as the thalamus or the spinal cord. We strongly believe that the data obtained from this proposal will provide a translational breakthrough in the treatment of these lethal tumors and open the door to future innovative clinical trials.