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Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma

Author

Listed:
  • Luuk Hooren

    (Uppsala University)

  • Alessandra Vaccaro

    (Uppsala University)

  • Mohanraj Ramachandran

    (Uppsala University)

  • Konstantinos Vazaios

    (Uppsala University)

  • Sylwia Libard

    (Uppsala University
    Uppsala University Hospital)

  • Tiarne Walle

    (Uppsala University)

  • Maria Georganaki

    (Uppsala University)

  • Hua Huang

    (Uppsala University)

  • Ilkka Pietilä

    (Uppsala University)

  • Joey Lau

    (Uppsala University)

  • Maria H. Ulvmar

    (Uppsala University)

  • Mikael C. I. Karlsson

    (Karolinska Institutet)

  • Maria Zetterling

    (Uppsala University)

  • Sara M. Mangsbo

    (Uppsala University)

  • Asgeir S. Jakola

    (Sahlgrenska University Hospital
    University of Gothenburg)

  • Thomas Olsson Bontell

    (University of Gothenburg
    Sahlgrenska University Hospital)

  • Anja Smits

    (Uppsala University
    University of Gothenburg)

  • Magnus Essand

    (Uppsala University)

  • Anna Dimberg

    (Uppsala University)

Abstract

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

Suggested Citation

  • Luuk Hooren & Alessandra Vaccaro & Mohanraj Ramachandran & Konstantinos Vazaios & Sylwia Libard & Tiarne Walle & Maria Georganaki & Hua Huang & Ilkka Pietilä & Joey Lau & Maria H. Ulvmar & Mikael C. I, 2021. "Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24347-7
    DOI: 10.1038/s41467-021-24347-7
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    Cited by:

    1. Spencer R. Rosario & Mark D. Long & Shanmuga Chilakapati & Eduardo Cortes Gomez & Sebastiano Battaglia & Prashant K. Singh & Jianmin Wang & Katy Wang & Kristopher Attwood & Suzanne M. Hess & AJ Robert, 2024. "Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Aman Mebrahtu & Ida Laurén & Rosanne Veerman & Gözde Güclüler Akpinar & Martin Lord & Alexandros Kostakis & Juan Astorga-Wells & Leif Dahllund & Anders Olsson & Oscar Andersson & Jonathan Persson & He, 2024. "A bispecific CD40 agonistic antibody allowing for antibody-peptide conjugate formation to enable cancer-specific peptide delivery, resulting in improved T Cell proliferation and anti-tumor immunity in," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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