Heidegger, S., Stritzke, F., Dahl, S., Dassler-Plenker, J., Joachim, L., Buschmann, D., Fan, K., Sauer, C.M., Ludwig, N., Winter, C., Enssle, S., Li, S., Perl, M., Gorgens, A., Haas, T., Orberg, E.T., Gottert, S., Wolfel, C., Engleitner, T., Cortes-Ciriano, I., Rad, R., Herr, W., Giebel, B., Ruland, J., Bassermann, F., Coch, C., Hartmann, G., Poeck, H. (2023). Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy. Cell Rep Med 4, 101171.
DOI: 10.1016/j.omto.2023.08.001
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.
