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

Heidegger, Simon, Stritzke, Florian, Dahl, Sarah, Daßler-Plenker, Juliane, Joachim, Laura, Buschmann, Dominik, Fan, Kaiji, Sauer, Carolin M, Ludwig, Nils, Winter, Christof, Enssle, Stefan, Li, Suqi, Perl, Markus, Görgens, André, Haas, Tobias, Orberg, Erik Thiele, Göttert, Sascha, Wölfel, Catherine, Engleitner, Thomas, Cortés-Ciriano, Isidro, Rad, Roland, Herr, Wolfgang, Giebel, Bernd, Ruland, Jürgen, Bassermann, Florian, Coch, Christoph, Hartmann, Gunther, Poeck, Hendrik (September 2023) Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy. Cell Reports Medicine, 4 (9). p. 101171. ISSN 2666-3791

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Abstract

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 Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > Extracellular vesicles diseases & disorders > cancer > drugs and therapies > Immunotherapy organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte diseases & disorders > cancer > cancer types > melanomas organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	DaBler-Plenker, Juliane
Communities:	CSHL labs > Egeblad lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	19 September 2023
Date Deposited:	11 Oct 2023 14:43
Last Modified:	10 Jan 2024 19:08
PMCID:	PMC10518594
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41176

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