TY - JOUR
T1 - IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma
AU - Collot, Raphaël
AU - Ruiz-Moreno, Cristian
AU - Honhoff, Celina
AU - van den Broek, Thijs J.M.
AU - Wezenaar, Amber K.L.
AU - Kloosterman, Daan J.
AU - Ariese, Hendrikus C.R.
AU - Johnson, Hannah
AU - Vervoort, Britt M.T.
AU - Jeiroshi, Amal
AU - Bunt, Jens
AU - van Ineveld, Ravian L.
AU - Bokobza, Emma
AU - Rebel, Heggert G.
AU - te Pas, Brigit M.
AU - Ringnalda, Femke C.A.
AU - van de Wetering, Marc
AU - Robe, Pierre A.
AU - Kool, Marcel
AU - Cochran, Jennifer R.
AU - Kranendonk, Mariëtte E.G.
AU - van Vuurden, Dannis G.
AU - Hulleman, Esther
AU - Wehrens, Ellen J.
AU - Zomer, Anoek
AU - Stunnenberg, Hendrik G.
AU - Rios, Anne C.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2026
Y1 - 2026
N2 - 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.
AB - 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.
KW - cancer-immune landscape
KW - diffuse midline glioma
KW - IGSF11-VISTA immune checkpoint
KW - microglia-cancer interaction
KW - spatial multi-omics profiling
UR - https://www.scopus.com/pages/publications/105028562536
U2 - 10.1016/j.ccell.2025.12.020
DO - 10.1016/j.ccell.2025.12.020
M3 - Article
C2 - 41576930
AN - SCOPUS:105028562536
SN - 1535-6108
VL - 44
SP - 641-657.e9
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -