Dendritic cell–derived exosomes for cancer therapy

Pitt, Jonathan M.; André, Fabrice; Amigorena, Sébastian; Soria, Jean‐Charles; Eggermont, Alexander M.M.; Kroemer, Guido; Zitvogel, Laurence

doi:10.1172/jci81137

Cited by 466 publications

(441 citation statements)

References 83 publications

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“…2,4 Several studies describe the involvement of exosomes in the modulation of both innate and adaptive immune response through different mechanisms. 1,3,46 As for NK cells, the immunomodulatory role of exosomes appears to be multi-faceted and dependent on the identity of both the exosomes-associated cargo end exosome releasing cells. 23,47 In this context, the inhibitory action of Tex on NK cell functions has been mostly attributed to TGF-b and/or NKG2D ligands associated to these vesicles.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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 IFNg production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/ HSP70-dependent manner. Interestingly, HSP70C 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 CD56 high NK cell subset is more responsive to exosome-induced IFNg 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…[23][24][25] Accordingly, to verify the possibility that DXR-induced exosomes are immune cell-derived, splenectomy was performed in mice prior to DXR treatment, and the serum exosome levels were then determined. The spleen is well known to play a crucial role in the systemic immune response.…”

Section: Effect Of Treatment With Dxr or Doxil ® On In Vivomentioning

confidence: 99%

Doxorubicin Expands <i>in Vivo</i> Secretion of Circulating Exosome in Mice

Emam

Ando

Lila

et al. 2018

Biological & Pharmaceutical Bulletin

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Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil ® affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil ® ) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil ® treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents.

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“…However, DC-based immunotherapy has several limitations. For example, molecular composition of DCs may change and is difficult to be defined (4). Tumor cells may secret soluble immunosuppressive cytokines that could convert immature DCs into tolerogenic DCs, which may activate Treg cells (5).…”

mentioning

confidence: 99%

“…Tumor cells may secret soluble immunosuppressive cytokines that could convert immature DCs into tolerogenic DCs, which may activate Treg cells (5). Live DCs are inconvenient for storage (4) and have to be produced locally with quality control issues.…”

mentioning

confidence: 99%