Using a multiomics approach on human and murine diffuse midline glioma samples, Collot, Ruiz-Moreno, Honhoff, et al. identified an MES pattern with mesenchymal tumor cells and blood-derived immune cells, and an AOO-pattern enriched with astrocyte, oligodendrocyte, and oligodendrocyte precursor-like cancer cell populations, alongside homeostatic-like microglia. Cancer cells in AOO niches expressed high levels of IGSF11 that signaled through VISTA on microglia. Targeting IGSF11–VISTA resulted in microglia-dependent, T cell-independent tumor reduction and survival benefit.
Contributed by Shishir Pant
ABSTRACT: Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with no curative treatment, and lacks a comprehensive understanding of immune-tumor cell interactions within their spatial context. Our multi-omics approach, integrating single-nuclei RNA sequencing, spatial transcriptomics, and high-dimensional imaging, utilizes patient samples and an experimental murine DMG model to unveil two spatially distinct regions. MES-patterns are defined by mesenchymal (MES) tumor cells and blood-derived immune cells, whereas AOO-patterns are enriched with astrocyte (AC)-, oligodendrocyte (OC)-, and oligodendrocyte precursor cell (OPC)-like cancer populations, alongside homeostatic-like microglia. The less-studied immune checkpoint, IGSF11, is primarily expressed by AOO-associated cancer cells, while its receptor VISTA is detected mainly in homeostatic microglia. Targeting IGSF11-VISTA results in tumor reduction and survival benefit, mediated by brain-resident microglia and independent of T cell infiltration. This positions IGSF11-VISTA as a promising immune checkpoint treatment axis to harness the local brain immune response against DMG.
Author Info: (1) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Princess Mxima Center for Pediatric Oncology, Utrecht,
Author Info: (1) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands. (3) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (4) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (5) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (6) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (7) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (8) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (9) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (10) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (11) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (12) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (13) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (14) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (15) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (16) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (17) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (18) Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. (19) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; University Medical Center Utrecht, Utrecht, the Netherlands; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany. (20) Department of Bioengineering, Stanford University Schools of Engineering and Medicine, Stanford, CA, USA. (21) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (22) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (23) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (24) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (25) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (26) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands. (27) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands. Electronic address: a.c.rios@prinsesmaximacentrum.nl.
