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

Autor: Anna Dimberg, Konstantinos Vazaios, Thomas Olsson Bontell, Hua Huang, Mikael C. I. Karlsson, Alessandra Vaccaro, Maria Georganaki, Tiarne van de Walle, Maria Zetterling, Asgeir Store Jakola, Magnus Essand, Sylwia Libard, Anja Smits, Sara M. Mangsbo, Mohanraj Ramachandran, Joey Lau, Luuk van Hooren, Maria H. Ulvmar, Ilkka Pietilä
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
medicine.medical_treatment
T-Lymphocytes
General Physics and Astronomy
Gene Expression
Cancer immunotherapy
Mice
0302 clinical medicine
Tumor Microenvironment
Medicine
Myeloid Cells
B-Lymphocytes
Multidisciplinary
CD11b Antigen
biology
Brain Neoplasms
Glioma
Phenotype
Integrin alpha M
030220 oncology & carcinogenesis
Cytokines
Female
Immunotherapy
Science
Antineoplastic Agents
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Immune system
Cell Line
Tumor
Animals
Humans
CD40 Antigens
Tumor microenvironment
Cancer och onkologi
CD40
business.industry
Immunology in the medical area
General Chemistry
medicine.disease
CNS cancer
Mice
Inbred C57BL
030104 developmental biology
Tertiary Lymphoid Structures
Cell culture
Immunologi inom det medicinska området
Cancer and Oncology
Immunoglobulin G
Cancer research
biology.protein
business
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
ISSN: 2041-1723
Popis: 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.
Agonistic CD40 antibodies (αCD40) have broad immunostimulatory properties, however their efficacy in glioma remains unclear. Here the authors show that αCD40 promotes the formation of tertiary lymphoid structures but does not improve survival and impairs the response to immune checkpoint blockade in murine glioma models.
Databáze: OpenAIRE
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