RIG-I activation induces the release of extracellular vesicles with antitumor activity

Daßler-Plenker, Juliane; Reiners, Katrin S.; Boorn, Jasper G. van den; Hansen, Hinrich P.; Putschli, Bastian; Barnert, Sabine; Schuberth-Wagner, Christine; Schubert, Rolf; Tüting, Thomas; Hallek, Michael; Schlee, Martin; Hartmann, Gunther; Strandmann, Elke Pogge von; Coch, Christoph

doi:10.1080/2162402x.2016.1219827

Cited by 48 publications

(43 citation statements)

References 56 publications

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“…BAT3/BAG6-expressing exosomes can stimulate cytokine release from NK cells upon interaction with NKp30, and BAT3/BAG6 expression by DC is responsible for activation NK cells to mediate the crosstalk with DC (49, 50). Similarly, RIG-I stimulation of melanoma cell lines was shown to trigger the extracellular release of BAT3/BAG6-containing vesicles that can stimulate NK cell cytolytic responses (51). In contrast, a soluble form of BAT3/BAG6 has been found at high levels in the plasma of CLL patients and can suppress NK cytolytic responses, apparently by blocking recognition of this and other ligands on tumor cells (82, 83).…”

Section: Ligands Of the Ncrsmentioning

confidence: 99%

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

et al. 2017

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The natural cytotoxicity receptor (NCR) family is constituted by NKp46, NKp44, and NKp30 in humans, which are expressed mainly on natural killer (NK) cells and are encoded by the ncr1, ncr2, and ncr3 genes, respectively. NCRs have classically been defined as activating receptors that trigger cytotoxicity and cytokine responses by NK cells upon engaging with ligands on tumor cells. Several new findings, however, have challenged this model and identified alternative mechanisms regulating the function of NCRs. Recent reports indicate that ligand matters, since the interaction of NKp44 with distinct ligands on target cells can either activate or inhibit NK cells. Also, the NCRs have been found to interact with distinct specificities to various heparan sulfate glycosaminoglycans, which are complex polysaccharides found in extracellular matrix or on cell surface heparan sulfate proteoglycans (HSPGs). The NCRs can engage with HSPGs in trans as a co-ligand on the target cells or in cis on the NK cell surface to regulate receptor–ligand interactions and NK cell activation. A number of splice variants of ncr2 and ncr3 have also been identified, and a predominant expression of certain variants results in inhibitory signaling through NKp44 and NKp30. Several recent studies have found that the selective expression of some of these inhibitory splice variants can significantly influence outcome in the contexts of cancer, infection, and pregnancy. These findings establish that NCR functions are more diverse than originally thought, and better understanding of their splice variant expression profiles and ligand interactions are needed to establish their functional regulation in the context of human health.

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Section: Ligands Of the Ncrsmentioning

confidence: 99%

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

et al. 2017

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“…15 More recently, RIG-I activation was shown to promote immunity against pancreatic cancer dependent on TGF-β1 silencing and CD8+ T cells, 16 and to be effective in tumor types exhibiting a high degree of cellular heterogeneity, such as glioblastoma. 18 In clinical hepatocellular carcinoma samples, low RIG-I expression is associated with poor survival as well as an unfavorable response to adjuvant therapy with IFN-α. 18 In clinical hepatocellular carcinoma samples, low RIG-I expression is associated with poor survival as well as an unfavorable response to adjuvant therapy with IFN-α.…”

Section: Introductionmentioning

confidence: 99%

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Wolf

Fiegl

Zeimet

et al. 2019

Intl Journal of Cancer

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Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum‐based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real‐time quantitative PCR to assess the expression of retinoic acid‐inducible gene‐I (RIG‐I) in primary tumor and healthy ovarian control tissues. RIG‐I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG‐I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG‐I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type‐II cancers and cancers with inactivating p53 mutations exhibited higher RIG‐I expression. RIG‐I levels were also elevated in cancers that recurred after remission or were platinum‐refractory. Survival analyses disclosed RIG‐I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG‐I expression in the tumor microenvironment, including interferon production and a distinct immune‐regulatory signature involving checkpoint molecules (PD‐L1/PD‐1), the RNA‐editing enzyme ADAR1 and the regulatory T cell‐specific transcription factor FoxP3. We conclude that high RIG‐I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG‐I expression may inform checkpoint blockade and/or RIG‐I agonistic targeting in a subset of high‐risk OC patients.

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“…31,32 Stimulation of NK cell activity by Tex was also shown to be dependent on NKp30 ligand BAT3 expressed on the exosome surface. 33,34 We endeavored to address whether exosomes released by MM cells exposed to sublethal doses of melphalan (MEL), a drug currently used in the clinical management of MM patients, affect NK cell effector functions. Herein, we show that MM-derived exosomes are capable of stimulating the production of IFNg by NK cells through a mechanism based on the activation of the NF-kB pathway in a TLR-2/HSP70-dependent manner.…”

Section: Introductionmentioning

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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RIG-I activation induces the release of extracellular vesicles with antitumor activity

Cited by 48 publications

References 56 publications

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

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

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