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@ARTICLE{Bessler:307548,
author = {N. Bessler and A. K. L. Wezenaar and H. C. R. Ariese and C.
Honhoff and N. Dommann and E. J. Wehrens and C. Ruiz Moreno
and T. J. M. van den Broek and R. V. U. Collot and D. J.
Kloosterman and F. Keramati and M. Roosen and S. de Blank
and E. van Vliet and M. Barrera Román and L. C. D. E. Gatti
and A. Ertürk and J. Kuball and Z. Sebestyén and M.
Kool$^*$ and S. Patrizi and E. Miele and A. Künkele and M.
E. G. Kranendonk and A. M. Cornel and S. Nierkens and C.
Mayer and H. G. Stunnenberg and A. Alemany and M. Alieva and
A. C. Rios},
title = {{D}e novo {H}3.3{K}27{M}-altered diffuse midline glioma in
human brainstem organoids to dissect {GD}2 {CAR} {T} cell
function.},
journal = {Nature cancer},
volume = {nn},
issn = {2662-1347},
address = {London},
publisher = {Nature Research},
reportid = {DKFZ-2026-00045},
pages = {nn},
year = {2026},
note = {#DKTKZFB26# / epub},
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.},
cin = {B062 / HD01},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41492091},
doi = {10.1038/s43018-025-01084-0},
url = {https://inrepo02.dkfz.de/record/307548},
}