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Data from Tumor-Derived Autophagosome Vaccine: Mechanism of Cross-Presentation and Therapeutic Efficacy
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Data from Tumor-Derived Autophagosome Vaccine: Mechanism of Cross-Presentation and Therapeutic Efficacy
Data from Tumor-Derived Autophagosome Vaccine: Mechanism of Cross-Presentation and Therapeutic Efficacy
YL
Yuhuan Li
Yuhuan Li
LW
Li-Xin Wang
Li-Xin Wang
PP
Puiyi Pang
Puiyi Pang
ZC
Zhihua Cui
Zhihua Cui
SA
Sandra Aung
Sandra Aung
DH
Daniel Haley
Daniel Haley
BF
Bernard A. Fox
Bernard A. Fox
WU
Walter J. Urba
Walter J. Urba
HH
Hong-Ming Hu
Hong-Ming Hu
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31 March 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1078-0432.c.6520361.v1
Abstract
Purpose: We previously reported that autophagy in tumor cells plays a critical role in cross-presentation of tumor antigens and that autophagosomes are efficient antigen carriers for cross-priming of tumor-reactive CD8+ T cells. Here, we sought to characterize further the autophagosome-enriched vaccine named DRibble (DRiPs-containing blebs), which is derived from tumor cells after inhibition of protein degradation, and to provide insights into the mechanisms responsible for their efficacy as a novel cancer immunotherapy.Experimental Design: DRibbles were characterized by Western blot and light or transmission electron microscopy. The efficiency of cross-presentation mediated by DRibbles was first compared with that of whole-tumor cells and pure proteins. The mechanisms of antigen cross-presentation by DRibbles were analyzed, and the antitumor efficacy of the DRibble vaccine was tested in 3LL Lewis lung tumors and B16F10 melanoma.Results: The DRibbles sequester both long-lived and short-lived proteins, including defective ribosomal products (DRiP), and damage-associated molecular pattern molecules exemplified by HSP90, HSP94, calreticulin, and HMGB1. DRibbles express ligands for CLEC9A, a newly described C-type lectin receptor expressed by a subset of conventional and plasmacytoid dendritic cells (DC), and cross-presentation was partially CLEC9A dependent. Furthermore, this autophagy-assisted antigen cross-presentation pathway involved both caveolae- and clathrin-mediated endocytosis and endoplasmic reticulum–associated degradation machinery. It depends on proteasome and TAP1, but not lysosome functions of antigen-presenting cells. Importantly, DCs loaded with autophagosome-enriched DRibbles can eradicate 3LL Lewis lung tumors and significantly delay the growth of B16F10 melanoma.Conclusions: These data documented the unique characteristics and potent antitumor efficacy of the autophagosome-based DRibble vaccine. The efficacy of DRibble cancer vaccine will be further tested in clinical trials. Clin Cancer Res; 17(22); 7047–57. ©2011 AACR.
Keywords
VACCINE
EFFICACY
CROSS PRESENTATION
AUTOPHAGY
AUTOPHAGOSOME ENRICHED
PROTEINS
TUMOR
ANTIGEN CROSS
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