Journal Article

DKFZ-2026-00045

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.

Bessler, N. ; Wezenaar, A. K. L. ; Ariese, H. C. R. ; Honhoff, C. ; Dommann, N. ; Wehrens, E. J. ; Ruiz Moreno, C. ; van den Broek, T. J. M. ; Collot, R. V. U. ; Kloosterman, D. J. ; Keramati, F. ; Roosen, M. ; de Blank, S. ; van Vliet, E. ; Barrera Román, M. ; Gatti, L. C. D. E. ; Ertürk, A. ; Kuball, J. ; Sebestyén, Z. ; Kool, M.DKFZ* ; Patrizi, S. ; Miele, E. ; Künkele, A. ; Kranendonk, M. E. G. ; Cornel, A. M. ; Nierkens, S. ; Mayer, C. ; Stunnenberg, H. G. ; Alemany, A. ; Alieva, M. ; Rios, A. C.

2026
Nature Research London

Abstract: 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.

Note: #DKTKZFB26# / epub

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Nature ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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