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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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1-s2.0-S221112472030886X-main.pdf (Any fulltext), 52MB
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 Creators:
Kozik, Patrycja1, Author
Gros, Marine1, Author
Itzhak, Daniel N.2, Author              
Joannas, Leonel1, Author
Heurtebise-Chretien, Sandrine1, Author
Krawczyk, Patrycja A.1, Author
Rodriguez-Silvestre, Pablo1, Author
Alloatti, Andres1, Author
Magalhaes, Joao Gamelas1, Author
Del Nery, Elaine1, Author
Borner, Georg H. H.2, Author              
Amigorena, Sebastian1, Author
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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Free keywords: MHC CLASS-I; DENDRITIC CELL MATURATION; CROSS-PRESENTATION; COPY-NUMBER; ANTIGEN; RESPONSES; COMPARTMENT; ACTIVATION; PROTEOME; REVEALS
 Abstract: 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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Language(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 22
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: CELL REPORTS
Source Genre: Journal
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Publ. Info: 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 32 (2) Sequence Number: 107905 Start / End Page: - Identifier: ISSN: 2211-1247