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

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-CirianoRoland Rad, Wolfgang Herr, Bernd Giebel, Jürgen Ruland, Florian Bassermann, Christoph Coch, Gunther Hartmann, Hendrik Poeck

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Article number101171
JournalCell Reports Medicine
Volume4
Issue number9
DOIs
StatePublished - 19 Sep 2023

Keywords

  • RIG-I
  • RNA
  • STING
  • cancer immunotherapy
  • cancer resistance
  • extracellular vesicles
  • innate immunity
  • nucleic acid receptors
  • personalized therapy

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