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Vulpis E, Loconte L, Peri A, et al. Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance. J Extracell Vesicles. 2022;11(1):e12176doi: 10.1002/jev2.12176.
Vulpis, E., Loconte, L., Peri, A., Molfetta, R., Caracciolo, G., Masuelli, L., Tomaipitinca, L., Peruzzi, G., Petillo, S., Petrucci, M. T., Fazio, F., Simonelli, L., Fionda, C., Soriani, A., Cerboni, C., Cippitelli, M., Paolini, R., Bernardini, G., Palmieri, G., Santoni, A., & Zingoni, A. (2022). Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance. Journal of extracellular vesicles, 11(1), e12176. https://doi.org/10.1002/jev2.12176
Vulpis, Elisabetta, et al. "Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance." Journal of extracellular vesicles vol. 11,1 (2022): e12176. doi: https://doi.org/10.1002/jev2.12176
Vulpis E, Loconte L, Peri A, Molfetta R, Caracciolo G, Masuelli L, Tomaipitinca L, Peruzzi G, Petillo S, Petrucci MT, Fazio F, Simonelli L, Fionda C, Soriani A, Cerboni C, Cippitelli M, Paolini R, Bernardini G, Palmieri G, Santoni A, Zingoni A. Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance. J Extracell Vesicles. 2022 Jan;11(1):e12176. doi: 10.1002/jev2.12176. PMID: 34973063; PMCID: PMC8720178.
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J Extracell Vesicles. 2022 Jan;11(1):e12176. doi: 10.1002/jev2.12176.

Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance.

Journal of extracellular vesicles

Elisabetta Vulpis, Luisa Loconte, Agnese Peri, Rosa Molfetta, Giulio Caracciolo, Laura Masuelli, Luana Tomaipitinca, Giovanna Peruzzi, Sara Petillo, Maria Teresa Petrucci, Francesca Fazio, Lucilla Simonelli, Cinzia Fionda, Alessandra Soriani, Cristina Cerboni, Marco Cippitelli, Rossella Paolini, Giovanni Bernardini, Gabriella Palmieri, Angela Santoni, Alessandra Zingoni

Affiliations

  1. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza' University of Rome, Rome, Italy.
  2. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  3. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
  4. Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy.
  5. Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
  6. Neuromed I.R.C.C.S.-Istituto Neurologico Mediterraneo, Pozzilli, Italy.

PMID: 34973063 PMCID: PMC8720178 DOI: 10.1002/jev2.12176

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes that play a key role in cancer immunosurveillance thanks to their ability to recognize and kill cancer cells. NKG2D is an activating receptor that binds to MIC and ULBP molecules typically induced on damaged, transformed or infected cells. The release of NKG2D ligands (NKG2DLs) in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle (EV) secretion allows cancer cells to evade NKG2D-mediated immunosurveillance. In this work, we investigated the immunomodulatory properties of the NKG2D ligand MICA*008 associated to distinct populations of EVs (i.e., small extracellular vesicles [sEVs] and medium size extracellular vesicles [mEVs]). By using as model a human MICA*008-transfected multiple myeloma (MM) cell line, we found that this ligand is present on both vesicle populations. Interestingly, our findings reveal that NKG2D is specifically involved in the uptake of vesicles expressing its cognate ligand. We provide evidence that MICA*008-expressing sEVs and mEVs are able on one hand to activate NK cells but, following prolonged stimulation induce a sustained NKG2D downmodulation leading to impaired NKG2D-mediated functions. Moreover, our findings show that MICA*008 can be transferred by vesicles to NK cells causing fratricide. Focusing on MM as a clinically and biologically relevant model of tumour-NK cell interactions, we found enrichment of EVs expressing MICA in the bone marrow of a cohort of patients. All together our results suggest that the accumulation of NKG2D ligands associated to vesicles in the tumour microenvironment could favour the suppression of NK cell activity either by NKG2D down-modulation or by fratricide of NK cell dressed with EV-derived NKG2D ligands.

© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

Keywords: MICA; NKG2D; Natural Killer cells; cancer; extracellular vesicles; immune evasion

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