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

Cell Reports
Patrycja KozikSebastian Amigorena

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.

Citations

Dec 2, 2020·The EMBO Journal·Sarah L CaddyLeo C James
Dec 8, 2020·Frontiers in Immunology·Patrycja A KrawczykPatrycja Kozik
Feb 23, 2021·Proteomics·Georg H H Borner
May 22, 2021·Journal for Immunotherapy of Cancer·Zining WangXiaojun Xia
Jun 4, 2021·Cell·Evangelos GiampazoliasCaetano Reis E Sousa
Oct 13, 2021·ChemPlusChem·Ziqi Lyu, Joseph C Genereux

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Datasets Mentioned

BETA
GSE109125

Methods Mentioned

BETA
flow cytometry
fractionation profiling
PCR
FCS

Key Resources (RRID) Mentioned

CVCL_WM78
CVCL_6277

Software Mentioned

GraphPad
Fiji
Adobe Photoshop
Tidyverse
MaxQuant
Proteomic Ruler
R
Prism
Significance A
Perseus

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