title: Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis.
abstract: Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here, we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma (MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome release from MM cells. MM cell-derived exosomes are capable of stimulating IFNγ production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-κB pathway in a TLR2/HSP70-dependent manner. Interestingly, HSP70+exosomes are primarily found in the bone marrow (BM) of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor microenvironment. We also provide evidence that the CD56highNK cell subset is more responsive to exosome-induced IFNγ production mediated by TLR2 engagement. All together, these findings suggest a novel mechanism of synergism between chemotherapy and antitumor innate immune responses based on the drug-promotion of nanovesicles exposing DAMPs for innate receptors.
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vulpis
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cecere
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Molfetta
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.affiliation: Istituto Italiano di Tecnologia, CLNS@Sapienza, Sapienza University of Rome , Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Peruzzi
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Caracciolo
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Palchetti
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Masuelli
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Rome, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Simonelli
authors.affiliation: GlaxoSmithKline Vaccine , Siena Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Abruzzese
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Division of Hematology, Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Paolini
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome, Rome, Italy; Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: Department of Molecular Medicine - Pasteur Italia Laboratory, Sapienza University of Rome , Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
keywords: DAMP; TLR; exosomes; immunotherapy; multiple myeloma; natural killer cells