Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy.
RIG-I
RNA
STING
cancer immunotherapy
cancer resistance
extracellular vesicles
innate immunity
nucleic acid receptors
personalized therapy
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
19 09 2023
19 09 2023
Historique:
received:
31
08
2022
revised:
04
05
2023
accepted:
03
08
2023
medline:
22
9
2023
pubmed:
2
9
2023
entrez:
1
9
2023
Statut:
ppublish
Résumé
Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose "reprogramming" of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy.
Identifiants
pubmed: 37657445
pii: S2666-3791(23)00324-5
doi: 10.1016/j.xcrm.2023.101171
pmc: PMC10518594
pii:
doi:
Substances chimiques
RNA
63231-63-0
Nucleic Acids
0
RNA, Neoplasm
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101171Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests S.H. has been a consultant for Bristol Myers-Squibb (BMS), Novartis, Merck, Abbvie, and Roche, has received research funding from BMS and Novartis, and is an employee of and holds equity interest in Roche/Genentech. A.G. is a consultant for and has equity interest in Evox Therapeutics Ltd. and is inventor on several patent applications related to extracellular vesicles. B.G. is a scientific advisory board member of Innovex Therapeutics SL, PL BioScience, and Mursla Ltd, consultant for FUJIFILM Wako Chemicals, and a founding director of Exosla Ltd. G.H. is inventor on a patent covering synthetic RIG-I ligand, and co-founder of Rigontec GmbH. H.P. is a consultant for Gilead, Abbvie, Pfizer, Novartis, Servier, and BMS, and has received research funding from BMS.
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