Melanoma-Derived Exosomes Induce PD-1 Overexpression and Tumor Progression via Mesenchymal Stem Cell Oncogenic Reprogramming

Gyukity-Sebestyen, Edina; Harmati, Mária; Dobra, Gabriella; Németh, István; Mihály, Johanna; Zvara, Ágnes; Hunyadi‐Gulyás, Éva; Katona, Róbert L.; Nagy, István; Horváth, Péter; Bálind, Árpád; Szkalisity, Ábel; Kovács, Mária; Pankotai, Tibor; Borsos, Barbara N.; Erdélyi, Miklós; Szegletes, Zsolt; Veréb, Zoltán; Buzás, Edit I.; Kemény, Lajos; Bı́ró, Tamás; Buzás, Krisztina

doi:10.3389/fimmu.2019.02459

Cited by 40 publications

(37 citation statements)

References 53 publications

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“…Exosomes from melanoma cells also take part in the immune-escape, either directly inhibiting immune effector cells or indirectly stimulating regulatory cells. The direct modulation of immune cells largely occurs in response to melanoma Exo-related inhibitory or pro-apoptotic signals and are mostly related to the exosomal expression of PD-L1 [32], while the indirect way involves the up-regulation of PD-1 by tumor accessory cells, such as mesenchymal stem cells (MSCs), which engulf the tumor microenvironment and restrain T-cell activation [33]. Moreover, Bland et al have recently discovered an alternative mechanism of melanoma derived-Exo, which affect the epigenetic landscape and mitochondrial respiration of cytotoxic T-cells.…”

Section: Role Of Exo In Melanoma Progressionmentioning

confidence: 99%

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

Mannavola

D’Oronzo

Cives

et al. 2019

IJMS

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Cutaneous melanoma shows a high metastatic potential based on its ability to overcome the immune system’s control. The mechanisms activated for these functions vary extremely and are also represented by the production of a number of extracellular vesicles including exosomes. Other vesicles showing a potential role in the melanoma progression include oncosomes and melanosomes and the majority of them mediate tumor processes including angiogenesis, immune regulation, and modifications of the micro-environment. Moreover, a number of epigenetic modifications have been described in melanoma and abundant production of altered microRNAs (mi-RNAs), non-coding RNAs, histones, and abnormal DNA methylation have been associated with different phases of melanoma progression. In addition, exosomes, miRNAs, and other molecular factors have been used as potential biomarkers reflecting disease evolution while others have been suggested to be potential druggable molecules for therapeutic application.

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Section: Role Of Exo In Melanoma Progressionmentioning

confidence: 99%

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

Mannavola

D’Oronzo

Cives

et al. 2019

IJMS

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“…The in-depth knowledge of the pleiotropic role of MTEX in the natural history of melanoma has a great potential clinical application in the disease diagnosis, treatment design, and prognosis of patient’s outcomes. MTEX are involved in a plethora of functions involved in initiation, progression, and metastasis of tumors, which is schematically depicted in Figure 2 (according to [ 26 , 37 , 73 , 74 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ,…”

Section: Biological Activity Of Mtexmentioning

confidence: 99%

“…This can be attributed to an increased level of PD-L1 in MTEX. This immunosuppression is driven by the interaction between PD-L1 carried by MTEX and PD-1 receptors on CD8 + T cells, leading to inhibition of T-cell functions [ 111 , 119 ]. MTEX are also enriched in Fas ligand (FasL) and APO2 ligand (APO2L)/TRAIL, both known as inducing factors of T cell-apoptosis [ 120 ].…”

Section: Biological Activity Of Mtexmentioning

confidence: 99%

“…The mitogen-activated protein kinase (MAPK) signaling pathway is activated during the MTEX-mediated EMT, with the involvement of Let-7i, a miRNA modulator of EMT [ 104 ]. Furthermore, acquisition of the EMT-like phenotype is enforced by expression of other key regulators of EMT induction, including ZEB2 and Snail 2 [ 119 , 129 ]. Upregulation of ZEB2 and Snail 2 in primary melanocytes after co-culture with MTEX was confirmed by Xiao et al This process was accompanied by decreased expression of E-cadherin and increased expression of vimentin [ 104 ].…”

Section: Biological Activity Of Mtexmentioning

confidence: 99%

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Signaling of Tumor-Derived sEV Impacts Melanoma Progression

Zebrowska

Widłak

Whiteside

et al. 2020

IJMS

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Small extracellular vesicles (sEV or exosomes) are nanovesicles (30–150 nm) released both in vivo and in vitro by most cell types. Tumor cells produce sEV called TEX and disperse them throughout all body fluids. TEX contain a cargo of proteins, lipids, and RNA that is similar but not identical to that of the “parent” producer cell (i.e., the cargo of exosomes released by melanoma cells is similar but not identical to exosomes released by melanocytes), possibly due to selective endosomal packaging. TEX and their role in cancer biology have been intensively investigated largely due to the possibility that TEX might serve as key component of a “liquid tumor biopsy.” TEX are also involved in the crosstalk between cancer and immune cells and play a key role in the suppression of anti-tumor immune responses, thus contributing to the tumor progression. Most of the available information about the TEX molecular composition and functions has been gained using sEV isolated from supernatants of cancer cell lines. However, newer data linking plasma levels of TEX with cancer progression have focused attention on TEX in the patients’ peripheral circulation as potential biomarkers of cancer diagnosis, development, activity, and response to therapy. Here, we consider the molecular cargo and functions of TEX as potential biomarkers of one of the most fatal malignancies—melanoma. Studies of TEX in plasma of patients with melanoma offer the possibility of an in-depth understanding of the melanoma biology and response to immune therapies. This review features melanoma cell-derived exosomes (MTEX) with special emphasis on exosome-mediated signaling between melanoma cells and the host immune system.

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“…The roles of soluble PD-1 and PD-L1 forms are being researched only outside of the HP context, but exosomal PD-L1 is a negative prognostic factor in melanoma [103]. Melanoma has been shown to recruit mesenchymal stem cells (MSC), induce PD-1 expression and transform them into melanoma-like pro-tumorigenic phenotype through exosomal signalling [104]. Neither the place of HP in this network nor the impact of intense ICB treatment on exosome production has been sufficiently assessed.…”

Section: Other Unexplored Mechanismsmentioning

confidence: 99%

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

Kocikowski

Dziubek

Parys

2020

Cancers

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Immune evasion is a major challenge for the development of successful cancer treatments. One of the known mechanisms is the expression of immune checkpoints (ICs)—proteins regulating the immune cells activation. The advent of immunotherapy using monoclonal antibodies (mAbs) to block the immune checkpoint receptor-ligand interaction brought about a landslide improvement in the treatment responses, leading to a prompt approval of such therapeutics. In recent years, it was discovered that a subset of patients receiving IC blockade treatment experienced a previously unknown pattern of treatment response called hyperprogression (HP), characterised by rapid deterioration on initialisation of the therapy. HP represents an urgent issue for clinicians and drug developers, while posing questions about the adequacy of the current clinical trial process. Here, we briefly summarise the state of knowledge and propose new directions for research into HP mechanisms, focusing on tumour-intrinsic signalling of IC proteins malignantly expressed by cancer. We also discuss the potential role of spontaneously occurring canine cancer in the assessment of immunotherapeutics, which can provide the missing link between murine and human studies.

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Melanoma-Derived Exosomes Induce PD-1 Overexpression and Tumor Progression via Mesenchymal Stem Cell Oncogenic Reprogramming

Cited by 40 publications

References 53 publications

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

Signaling of Tumor-Derived sEV Impacts Melanoma Progression

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

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