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  Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity

Kozik, P., Gros, M., Itzhak, D. N., Joannas, L., Heurtebise-Chretien, S., Krawczyk, P. A., et al. (2020). Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity. CELL REPORTS, 32(2): 107905. doi:10.1016/j.celrep.2020.107905.

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 Urheber:
Kozik, Patrycja1, Autor
Gros, Marine1, Autor
Itzhak, Daniel N.2, Autor           
Joannas, Leonel1, Autor
Heurtebise-Chretien, Sandrine1, Autor
Krawczyk, Patrycja A.1, Autor
Rodriguez-Silvestre, Pablo1, Autor
Alloatti, Andres1, Autor
Magalhaes, Joao Gamelas1, Autor
Del Nery, Elaine1, Autor
Borner, Georg H. H.2, Autor           
Amigorena, Sebastian1, Autor
Affiliations:
1external, ou_persistent22              
2Borner, Georg / Systems Biology of Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society, ou_3060205              

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Schlagwörter: MHC CLASS-I; DENDRITIC CELL MATURATION; CROSS-PRESENTATION; COPY-NUMBER; ANTIGEN; RESPONSES; COMPARTMENT; ACTIVATION; PROTEOME; REVEALS
 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2020
 Publikationsstatus: Online veröffentlicht
 Seiten: 22
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000548535600018
DOI: 10.1016/j.celrep.2020.107905
 Art des Abschluß: -

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Titel: CELL REPORTS
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA : CELL PRESS
Seiten: - Band / Heft: 32 (2) Artikelnummer: 107905 Start- / Endseite: - Identifikator: ISSN: 2211-1247