Neutralization of acyl-CoA-binding protein attenuates glucocorticoid-mediated suppression of cancer immunosurveillance
Abstract
Glucocorticoids (GCs) are potent immunosuppressive agents that compromise anticancer immune responses, yet the molecular mediators of this effect remain incompletely understood. Here, we identify the acyl-CoA-binding protein/diazepam-binding inhibitor (ACBP/DBI) as a critical effector of the GC-induced suppression of tumor immunosurveillance and immunotherapy efficacy. Using orthotopic murine models of breast cancer, non–small cell lung cancer, and cutaneous fibrosarcoma, we show that corticosterone (CORT) accelerates tumor progression and abrogates therapeutic responses to immunogenic chemotherapy and PD-1 blockade. Genetic ablation or monoclonal antibody (mAb)-mediated neutralization of ACBP/DBI prevents immunosuppression by CORT, restoring both natural and therapy-enhanced antitumor immunity in a T cell–dependent manner. Mechanistically, CORT induces Tsc22d3 expression in dendritic cells, impairs type I interferon signaling, and reduces antigen presentation capacity, which all can be reversed by ACBP/DBI neutralization. The immunosuppressive activity of GCs and the immunostimulatory function of anti-ACBP/DBI mAb converge on Tsc22d3 expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific Tsc22d3 -deficient mice. These findings reveal ACBP/DBI as a central mediator of GC-induced immune evasion and suggest its neutralization as a therapeutic strategy to restore anticancer immunity during endogenous or iatrogenic GC exposure.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Hui Pan
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai 200032, China
Zhe Shen
Department of Neurobiology, School of Biological Sciences, University of California
Liwei Zhao
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université
Peng Liu
Ziqi Jin
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology
Eléonore Piard
Université Paris-Saclay, Gustave Roussy, ClinicoBiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy
Enfu Xue
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université
Flavia Lambertucci
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Gautier Stoll
Computational Biology and Integrative Genomics of Cancer, INSERM U1331 Computational Oncology, Institut Curie, PSL Research University, Mines Paris Tech
Vincent Carbonnier
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Léa Montégut
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Sabrina Forveille
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université
Maria Chiara Maiuri
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université
Oliver Kepp
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université
Laurence Zitvogel
Yuting Ma
National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College
Isabelle Martins
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Guido Kroemer