%0 Journal Article
%A Bessler, Nils
%A Wezenaar, Amber K L
%A Ariese, Hendrikus C R
%A Honhoff, Celina
%A Dommann, Noëlle
%A Wehrens, Ellen J
%A Ruiz Moreno, Cristian
%A van den Broek, Thijs J M
%A Collot, Raphaël V U
%A Kloosterman, Daan J
%A Keramati, Farid
%A Roosen, Mieke
%A de Blank, Sam
%A van Vliet, Esmée
%A Barrera Román, Mario
%A Gatti, Lucrezia C D E
%A Ertürk, Ali
%A Kuball, Jürgen
%A Sebestyén, Zsolt
%A Kool, Marcel
%A Patrizi, Sara
%A Miele, Evelina
%A Künkele, Annette
%A Kranendonk, Mariëtte E G
%A Cornel, Annelisa M
%A Nierkens, Stefan
%A Mayer, Christian
%A Stunnenberg, Hendrik G
%A Alemany, Anna
%A Alieva, Maria
%A Rios, Anne C
%T De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.
%J Nature cancer
%V nn
%@ 2662-1347
%C London
%I Nature Research
%M DKFZ-2026-00045
%P nn
%D 2026
%Z #DKTKZFB26# / epub
%X Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41492091
%R 10.1038/s43018-025-01084-0
%U https://inrepo02.dkfz.de/record/307548