INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Daniel N. Itzhak
Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
Leonel Joannas
INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Sandrine Heurtebise-Chrétien
INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Patrycja A. Krawczyk
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
Pablo Rodríguez-Silvestre
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
Andrés Alloatti
INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Joao Gamelas Magalhaes
INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Elaine Del Nery
Institut Curie, PSL Research University, Department of Translational Research-Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France
Georg H.H. Borner
Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
Sebastian Amigorena
INSERM U932, PSL Research University, Institut Curie, 75005 Paris, France
Summary: Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers.
