TY  - JOUR
AU  - Bessler, Nils
AU  - Wezenaar, Amber K L
AU  - Ariese, Hendrikus C R
AU  - Honhoff, Celina
AU  - Dommann, Noëlle
AU  - Wehrens, Ellen J
AU  - Ruiz Moreno, Cristian
AU  - van den Broek, Thijs J M
AU  - Collot, Raphaël V U
AU  - Kloosterman, Daan J
AU  - Keramati, Farid
AU  - Roosen, Mieke
AU  - de Blank, Sam
AU  - van Vliet, Esmée
AU  - Barrera Román, Mario
AU  - Gatti, Lucrezia C D E
AU  - Ertürk, Ali
AU  - Kuball, Jürgen
AU  - Sebestyén, Zsolt
AU  - Kool, Marcel
AU  - Patrizi, Sara
AU  - Miele, Evelina
AU  - Künkele, Annette
AU  - Kranendonk, Mariëtte E G
AU  - Cornel, Annelisa M
AU  - Nierkens, Stefan
AU  - Mayer, Christian
AU  - Stunnenberg, Hendrik G
AU  - Alemany, Anna
AU  - Alieva, Maria
AU  - Rios, Anne C
TI  - De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.
JO  - Nature cancer
VL  - nn
SN  - 2662-1347
CY  - London
PB  - Nature Research
M1  - DKFZ-2026-00045
SP  - nn
PY  - 2026
N1  - #DKTKZFB26# / epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41492091
DO  - DOI:10.1038/s43018-025-01084-0
UR  - https://inrepo02.dkfz.de/record/307548
ER  -