Tumor‐derived extracellular vesicles activate primary monocytes

Gärtner, Kathrin; Battke, Christina; Dünzkofer, Judith; Hüls, Corinna; Neubeck, Bettina von; Kellner, Mar‐ kus; Fiestas, Elena; Fackler, Susanne; Lang, Stephan; Zeidler, Reinhard

doi:10.1002/cam4.1465

Cited by 21 publications

(19 citation statements)

References 27 publications

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“…Tumor-derived soluble mediators such as chemokines (CCL2, CCL5, CXCL12), colony-stimulating factor-1 (CSF-1), TGF-β, IL-10, prostaglandin E2 (PGE2) and metabolites (lactate) likely contribute to the development of TAMs with M2-like phenotype and tumor-promoting properties [16]. Recent studies indicated that, in addition to soluble factors, tumor-derived exosomes could also modulate macrophage cytokine profile and phenotype [17–21]. However, little is known about how TRAPs affect macrophage polarization and function in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1

Zhang¹,

Liu²,

Gao³

et al. 2018

j. immunotherapy cancer

130

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BackgroundTumor-associated macrophages (TAMs) facilitate tumor progression via establishment of an immunosuppressive tumor microenvironment (TME). However, it is poorly understood how tumor cells could functionally modulate TAMs. Our previous work indicated that tumor cell-released autophagosomes (TRAPs), a type of LC3-II+ double-membrane extracellular vesicles (EVs) was sufficient to suppress anti-tumor immune responses by inducing IL-10-producing B cells and immune suppressive neutrophils. Here, we hypothesized that TRAPs may participate in regulating macrophage polarization.MethodsTRAPs isolated from multiple murine tumor cell lines and pleural effusions or ascites of cancer patients were incubated with bone marrow-derived macrophages (BMDMs) and monocytes, respectively. Cellular phenotypes were examined by flow cytometry, ELISA and quantitative PCR. TRAPs treated BMDMs were tested for the ability to suppress T-cell proliferation in vitro, and for promotion of tumor growth in vivo. Transwell chamber and neutralization antibodies were added to ascertain the inhibitory molecules expressed on BMDMs exposed to TRAPs. Knockout mice were used to identify the receptors responsible for TRAPs-induced BMDMs polarization and the signaling mechanism was examined by western blot. Autophagy-deficient tumors were profiled for phenotypic changes of TAMs and IFN-γ secretion of T cells by flow cytometry. The phenotype of monocytes from pleural effusions or ascites of cancer patients was assessed by flow cytometry.ResultsTRAPs converted macrophages into an immunosuppressive M2-like phenotype characterized by the expression of PD-L1 and IL-10. These macrophages inhibited the proliferation of both CD4+ and CD8+ T cells in vitro, and promoted tumor growth mainly through PD-L1 in vivo. TRAPs-induced macrophage polarization was dependent on TLR4-mediated MyD88-p38-STAT3 signaling. In vivo studies indicated that disruption of autophagosome formation in B16F10 cells by silencing the autophagy gene Beclin1 resulted in a remarkable delay in tumor growth, which was associated with reduced autophagosome secretion, TAMs reprogramming and enhanced T cell activation. Moreover, the levels of LC3B+ EVs appeared to correlate significantly with up-regulation of PD-L1 and IL-10 in matched monocytes from effusions or ascites of cancer patients, and TRAPs isolated from these samples could also polarize monocytes to an M2-like phenotype with increased expression of PD-L1, CD163 and IL-10, decreased expression of HLA-DR, and T cell-suppressive function.ConclusionsThese findings suggest the TRAPs-PD-L1 axis as a major driver of immunosuppression in the TME by eliciting macrophage polarization towards an M2-like phenotype, and highlight the potential novel therapeutic approach of simultaneously targeting autophagy and PD-L1.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0452-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1

Zhang¹,

Liu²,

Gao³

et al. 2018

j. immunotherapy cancer

130

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“…In line with these results, Bretz et al demonstrated that the stimulation of THP-1 cells by exosomes of cancerous and non-cancerous origin occurred through a TLR (toll-like receptor) dependent mechanism [42]. Furthermore, tumor-derived sEVs have been shown to activate primary monocytes [43]. We used sEVs isolated from a well-established melanoma cell line (A375), as well as from patient-derived primary melanoma cell lines.…”

Section: Discussionmentioning

confidence: 88%

Melanoma-Derived Extracellular Vesicles Bear the Potential for the Induction of Antigen-Specific Tolerance

Duechler

Czernek

Pęczek

et al. 2019

Cells

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Background: Cancer-induced immunosuppression is antigen-specific rather than systemic and the mechanisms for the antigen specificity are incompletely understood. Here we explore the option that tumor-associated antigens (TAAs) may be transferred to antigen-presenting cells (APCs), together with immunosuppressive molecules, through cancer-derived small extracellular vesicles (sEVs), such as exosomes. Stimulation of a suppressive phenotype in the very same APCs that take up TAAs may yield antigen-specific tolerance. Methods: sEVs isolated from patient-derived or well-established melanoma cell lines were used to demonstrate the transfer of major histocompatibility complex (MHC) molecules to the surface of APCs. The immunosuppressive influence of sEVs was assessed by flow cytometry analysis of activation markers, cytokine expression, and mixed lymphocyte reactions. Results: MHC class I molecules were transferred from melanoma cells to the cell surface of APCs by sEVs. Concomitantly, CD86 and CD40 co-stimulatory molecules were down-regulated and IL-6 production was strongly induced. TGF-β transported by sEVs contributed to the promotion of a suppressive phenotype of APCs. Conclusion: The presented results indicate the existence of a hitherto undescribed mechanism that offers an explanation for antigen-specific tolerance induction mediated by cancer-derived sEVs.

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“…It is widely recognized that abnormalities in cytokine expression are implicated in tumorigenesis as they promote growth, reduce apoptosis and facilitate invasion and metastasis of cancer cells 41,42 . Moreover, it has been reported that tumor‐derived EVs induce in primary monocytes an activated phenotype, which is also observed in tumor‐associated macrophages 43 .…”

Section: Discussionmentioning

confidence: 95%

Toll-like Receptor-4 Activation Boosts the Immunosuppressive Properties of Tumor Cells-derived Exosomes

Domenis

Cifù

Marino

et al. 2019

Sci Rep

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The biology of tumor-derived exosomes (TEX) is only partially understood and much remains to be studied in order to define the effect that the tumor microenvironment or the activation of tumor cells exerts on their composition and functions. Increased expression and activity of toll-like receptor 4 (TLR4) in chronic infectious and inflammatory conditions is related with cancer progression: its activation induces an inflammatory signaling that increases the tumorigenic potential of cancer cells promoting their immune evasion. We investigated the immune modulatory properties of TEX released upon cell TLR4 activation, and we found that, although differences were observed depending on the type of the tumor, the treatment influences TEX composition and boosts their immunosuppressive ability. Our results suggest that the activation of TLR4 supports tumor progression by stimulating the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance and probably even play a role in the metastatic process.

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Tumor‐derived extracellular vesicles activate primary monocytes

Cited by 21 publications

References 27 publications

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1

Melanoma-Derived Extracellular Vesicles Bear the Potential for the Induction of Antigen-Specific Tolerance

Toll-like Receptor-4 Activation Boosts the Immunosuppressive Properties of Tumor Cells-derived Exosomes

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