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Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy

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 c...

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Main Authors: Heidegger, Simon (Author) , Stritzke, Florian (Author) , Dahl, Sarah (Author) , Daßler-Plenker, Juliane (Author) , Joachim, Laura (Author) , Buschmann, Dominik (Author) , Fan, Kaiji (Author) , Sauer, Carolin M. (Author) , Ludwig, Nils (Author) , Winter, Christof (Author) , Enssle, Stefan (Author) , Li, Suqi (Author) , Perl, Markus (Author) , Görgens, André (Author) , Haas, Tobias (Author) , Orberg, Erik Thiele (Author) , Göttert, Sascha (Author) , Wölfel, Catherine (Author) , Engleitner, Thomas (Author) , Cortés-Ciriano, Isidro (Author) , Rad, Roland (Author) , Herr, Wolfgang (Author) , Giebel, Bernd (Author) , Ruland, Jürgen (Author) , Bassermann, Florian (Author) , Coch, Christoph (Author) , Hartmann, Gunther (Author) , Poeck, Hendrik (Author)
Format: Article (Journal)
Language:English
Published: 19 September 2023
In: Cell reports. Medicine
Year: 2023, Volume: 4, Issue: 9, Pages: 1-25
ISSN:2666-3791
DOI:10.1016/j.xcrm.2023.101171
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.xcrm.2023.101171
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2666379123003245
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Author Notes:Simon Heidegger, Florian Stritzke, Sarah Dahl, Juliane Daßler-Plenker, Laura Joachim, Dominik Buschmann, Kaiji Fan, Carolin M. Sauer, Nils Ludwig, Christof Winter, Stefan Enssle, Suqi Li, Markus Perl, André Görgens, Tobias Haas, Erik Thiele Orberg, Sascha Göttert, Catherine Wölfel, Thomas Engleitner, Isidro Cortés-Ciriano, Roland Rad, Wolfgang Herr, Bernd Giebel, Jürgen Ruland, Florian Bassermann, Christoph Coch, Gunther Hartmann, and Hendrik Poeck
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Summary: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.
Item Description:Online verfügbar: 31. August 2023, Artikelversion: 19. September 2023
Gesehen am 26.01.2024
Physical Description:Online Resource
ISSN:2666-3791
DOI:10.1016/j.xcrm.2023.101171

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