Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift

Park, Jung Eun; Dutta, Bamaprasad; Tse, Shun Wilford; Gupta, Nikhil; Tan, Chee Fan; Low, Jee Keem; Yeoh, Kheng Wei; Kon, Oi Lian; Tam, James P.; Sze, Siu Kwan

doi:10.1038/s41388-019-0782-x

Cited by 246 publications

(225 citation statements)

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“…60 Moreover under hypoxia, murine melanoma tumors secrete exosomes able to up-regulate oxidative phosphorylation in bone marrow-derived macrophages, inducing their polarisation towards F4/80 + CD206 high M2-MΦ, favoring tumor development. 61 Outstandingly, our data suggest that tumorderived factors affect monocytes in the bloodstream of patient. Microarray analysis revealed that patient monocytes display a distinct transcriptome by down-regulating genes involved in monocyte differentiation and immune stimulation, while producing fewer inflammatory cytokines than HD monocytes and these results have been confirmed in an independent set of transcriptomic data from patients with primary BC.…”

Section: Discussionmentioning

confidence: 72%

“…In phyllode malignant breast tumors, a particular BC subtype, CCL5 produced by tumor cells promotes the polarisation of TAMs into IL18 + producers, via the AKT pathway leading to a positive feedback for tumor promotion and aggressiveness . Moreover under hypoxia, murine melanoma tumors secrete exosomes able to up‐regulate oxidative phosphorylation in bone marrow‐derived macrophages, inducing their polarisation towards F4/80 + CD206 high M2‐MΦ, favoring tumor development …”

Section: Discussionmentioning

confidence: 99%

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CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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Objectives The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. Methods Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients’ blood monocytes profiles. Results We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163highCD86lowIL‐10high M2‐like MΦ that strongly suppressed CD4+ T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. Conclusion Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163high TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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“…In contrast to many other tumor types, M2 polarized macrophages, reduce metastasis and improve survival in high-grade OS patients. Macrophage polarization is also able to modulate iron sequestration and release [24][25][26][27][28].…”

Section: Research Papermentioning

confidence: 99%

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

et al. 2020

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Tumor-associated macrophages and their alternative activation states together with cytokines and growth factors trapped in tumor microenvironment contribute to the progression of OS. In contrast to other tumor types, M2 polarized macrophages, reduce metastasis and improve survival in osteosarcoma patients. Mifamurtide is an immunomodulatory drug given together with standard adjuvant chemotherapy in high-grade osteosarcoma to improve outcome. Macrophages obtained from peripheral blood mononucleated cells of healthy donors and MG63 cells were cultured alone and together, and treated with Mifamurtide. We analyzed the effects of Mifamurtide on macrophage polarization and on MG63 proliferation, migration and differentiation, evaluating the expression of M1/M2 and osteoblast markers and molecules involved in metastasis and proliferation pathways. Our data suggest that Mifamurtide, switching macrophage polarization towards a TAM-like intermediate M1/M2 phenotype, may modulate the delicate balance between pro-inflammatory and immunomodulatory macrophage functions. Moreover, Mifamurtide may inhibit the cellular proliferation and induce the tumor cell differentiation, probably through the down regulation of pSTAT3, pAKT and IL-17R.

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“…Park and colleagues found that hypoxia contributes to the EV-mediated M2 polarization of TAM. Authors found that EVs released by hypoxic tumor cells were enriched in immunomodulatory proteins and chemokines including CSF-1, CCL2, FTH, FTL, and TGFβ that, together with the EVs-associated miRNAs, influence macrophage recruitment and promote M2-like polarization [74]. In addition to microRNAs, it was largely described that EVs carry functional long noncoding RNA (lncRNAs) [75] that contributed to the TEV-mediated tumor progression [76].…”

Section: Tevs and Macrophage Polarizationmentioning

confidence: 99%

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

Raimondo

Pucci

Alessandro

et al. 2020

IJMS

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The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

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Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift

Cited by 246 publications

References 74 publications

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

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Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift

Cited by 246 publications

References 74 publications

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

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CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes