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
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 imm...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-03-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1279372 |
| _version_ | 1811339442373263360 |
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| author | Elisabetta Vulpis Francesca Cecere Rosa Molfetta Alessandra Soriani Cinzia Fionda Giovanna Peruzzi Giulio Caracciolo Sara Palchetti Laura Masuelli Lucilla Simonelli Ugo D'Oro Maria Pia Abruzzese Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Alessandra Zingoni |
| author_facet | Elisabetta Vulpis Francesca Cecere Rosa Molfetta Alessandra Soriani Cinzia Fionda Giovanna Peruzzi Giulio Caracciolo Sara Palchetti Laura Masuelli Lucilla Simonelli Ugo D'Oro Maria Pia Abruzzese Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Alessandra Zingoni |
| author_sort | Elisabetta Vulpis |
| collection | DOAJ |
| description | 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 CD56high NK 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. |
| first_indexed | 2024-04-13T18:26:40Z |
| format | Article |
| id | doaj.art-7fbd108914b34b8aad9745f7c2cae788 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-13T18:26:40Z |
| publishDate | 2017-03-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-7fbd108914b34b8aad9745f7c2cae7882022-12-22T02:35:14ZengTaylor & Francis GroupOncoImmunology2162-402X2017-03-016310.1080/2162402X.2017.12793721279372Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axisElisabetta Vulpis0Francesca Cecere1Rosa Molfetta2Alessandra Soriani3Cinzia Fionda4Giovanna Peruzzi5Giulio Caracciolo6Sara Palchetti7Laura Masuelli8Lucilla Simonelli9Ugo D'Oro10Maria Pia Abruzzese11Maria Teresa Petrucci12Maria Rosaria Ricciardi13Rossella Paolini14Marco Cippitelli15Angela Santoni16Alessandra Zingoni17Sapienza University of RomeSapienza University of RomeSapienza University of RomeSapienza University of RomeSapienza University of RomeIstituto Italiano di Tecnologia, CLNS@Sapienza, Sapienza University of RomeSapienza University of RomeSapienza University of RomeSapienza University of RomeSapienza University of RomeGlaxoSmithKline VaccineSapienza University of RomeSapienza University of RomeDivision of HematologySapienza University of RomeSapienza University of RomeSapienza University of RomeSapienza University of RomeExosomes 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 CD56high NK 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.http://dx.doi.org/10.1080/2162402X.2017.1279372dampexosomesimmunotherapymultiple myelomanatural killer cellstlr |
| spellingShingle | Elisabetta Vulpis Francesca Cecere Rosa Molfetta Alessandra Soriani Cinzia Fionda Giovanna Peruzzi Giulio Caracciolo Sara Palchetti Laura Masuelli Lucilla Simonelli Ugo D'Oro Maria Pia Abruzzese Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Alessandra Zingoni 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 OncoImmunology damp exosomes immunotherapy multiple myeloma natural killer cells tlr |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | damp exosomes immunotherapy multiple myeloma natural killer cells tlr |
| url | http://dx.doi.org/10.1080/2162402X.2017.1279372 |
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