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<p>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.</p>

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De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Nils Bessler,
  • Amber K. L. Wezenaar,
  • Hendrikus C. R. Ariese,
  • Celina Honhoff,
  • Noëlle Dommann,
  • Ellen J. Wehrens,
  • Cristian Ruiz Moreno,
  • Thijs J. M. van den Broek,
  • Raphaël V. U. Collot,
  • Daan J. Kloosterman,
  • Farid Keramati,
  • Mieke Roosen,
  • Sam de Blank,
  • Esmée van Vliet,
  • Mario Barrera Román,
  • Lucrezia C. D. E. Gatti,
  • Ali Ertürk,
  • Jürgen Kuball,
  • Zsolt Sebestyén,
  • Marcel Kool,
  • Sara Patrizi,
  • Evelina Miele,
  • Annette Künkele,
  • Mariëtte E. G. Kranendonk,
  • Annelisa M. Cornel,
  • Stefan Nierkens,
  • Christian Mayer,
  • Hendrik G. Stunnenberg,
  • Anna Alemany,
  • Maria Alieva,
  • Anne C. Rios

摘要

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.