Abstract Diffuse midline gliomas (DMGs) are very aggressive central nervous system tumors that occur mainly in children and adolescents. Most DMGs develop in the brainstem but can also be found in the thalamus and spinal cord. Despite more than fifty years of clinical trials, the outcome for DMG patients remains extremely poor, being radiotherapy, the standard of care, just palliative. Thus, new therapeutic approaches, including immunotherapy, are being developed for these patients. However, the lack of spinal cord models has led to most preclinical research using tumor models that grow in the pons or the thalamus. This highlights the necessity of developing spinal cord DMG models that enable us to test and study advanced therapies in this specific location to study alternative therapies. In this work, we have generated an orthotopic and immunocompetent model of spinal cord DMG by injecting murine DMG cells carrying the H3K27M driver mutation directly under the T2 vertebra of mice. This model develops neurologic symptoms such as hemiplegia and hemiparesis as they occur in the patients. The characterization of the tumor immune microenvironment by scRNAseq showed a high infiltration of macrophages and microglia (TAMs) that express TIM-3, a non-classical immune checkpoint. Therefore, we tested the treatment with a TIM-3 antagonistic antibody, which we have previously described as effective in pontine DMG-bearing mice. Mice were treated with one intraventricular dose of the antibody followed by several intraperitoneal administrations. The therapy was well tolerated and reduced the tumor size, increasing the median overall survival of mice. We characterized the immune response to this treatment both in the tumor and in the tumor-draining lymph nodes at different stages of progression. We believe that these results open a path for a deeper characterization of the spinal cord DMG TIME and for the development and testing of new therapeutic approaches for this disease.
Osuna et al. (Fri,) studied this question.