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

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. Karlsson, Maria Zetterling, Sara M. Mangsbo, Asgeir S. Jakola, Thomas Olsson Bontell, Anja Smits, Magnus Essand and Anna Dimberg ()
Additional contact information
Luuk Hooren: Uppsala University
Alessandra Vaccaro: Uppsala University
Mohanraj Ramachandran: Uppsala University
Konstantinos Vazaios: Uppsala University
Sylwia Libard: Uppsala University
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
Thomas Olsson Bontell: University of Gothenburg
Anja Smits: Uppsala University
Magnus Essand: Uppsala University
Anna Dimberg: Uppsala University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24347-7

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