The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

The biology, function, and biomedical applications of exosomes

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

/pdf/role-of-the-tumor-microenvironment-in-pd-l1-pd-1-mediated-4cvw6htifn.pdf

Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape.

Exosomes in cancer development, metastasis, and immunity.

The interaction of programmed cell death 1 ligand 1 (PDL1) with its receptor programmed cell death 1 (PD1) inhibits T cell responses, and blockade of this interaction has proven to be an effective immunotherapy for several different cancers. PDL1 can be expressed on the surface of tumour cells, immune cells and other cells in the tumour microenvironment but is also found in extracellular forms. Recent studies have explored the importance of different forms of extracellular PDL1, such as on exosomes or as a freely soluble protein, and have shown that PDL1-expressing exosomes can inhibit antitumour immune responses. In patients with melanoma, exosomal PDL1 is also a marker of immune activation early after initiation of therapy with PD1-blocking antibodies and predicts a clinical response to PD1 blockade. In this Progress article, we highlight recent insights into the role of exosomal PDL1 in immune oncology and how it may be useful as a biomarker for the management of cancer or to define a subset of patients who would benefit from therapeutics that block exosome production. Freeman and colleagues draw our attention to the existence of different forms of PDL1 — cell bound and various extracellular forms. Recent studies show that PDL1 on exosomes can inhibit antitumour immune responses and may be a useful biomarker for the management of cancer immunotherapy.

The importance of exosomal PDL1 in tumour immune evasion

Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment. 

/pdf/emerging-role-of-exosomes-in-cancer-progression-and-tumor-3ue2tzgw.pdf

Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

INTRODUCTION: Exosomes secreted by cancer cells have pleiotropic functions, and can promote autocrine signaling to distant cells. Elucidating the mechanistic modulation of the immune system by these exosomes provides insight into potential biomarkers for detection, recurrence, and response, and identifies potential new therapeutic targets. METHODS: Exosomes were isolated from human glioblastoma stem cells (GSC) and fibroblasts (control) using differential centrifugation. Fluorescent-labeled exosomes were co-cultured with human peripheral blood mononuclear cells (PBMCs). Flow cytometry and confocal microscopy methods were utilized to determine the ability of immune cells to uptake exosomes and to evaluate subsequent intracellular trafficking. The exosomal protein and RNA content was analyzed by mass spectrometry and Nanostring Counter System, respectively. The phenotypic and functional skewing of the monocyte lineage was analyzed after exposing these cells to exosomes. The cytokine array was used to analyze the cytokines generated following treatment of human normal monocytes with exosomes. RESULTS: The GSC-secreted exosomes were preferentially absorbed by CD14+ monocytes and Gr-1+ derived myeloid cells isolated from healthy volunteers and/or glioblastoma patients. When activated, CD4+ and CD8+ T cells could also uptake GSC-secreted exosomes. Confocal microscopy revealed that only monocytes could internalize GSC-secreted exosomes but not fibroblast-secreted exosomes. The exposure to GSC-secreted exosomes induces a phenotypic change in monocytes and prevents them from undergoing apoptosis. GSC-secreted exosomes, but not the fibroblast-secreted exosomes, increased expression of CD163, CD206, and decreased expression of MHC class II. Monocytes treated with GSC-secreted exosomes release IL-6, IL-1RA, CCL3, and CCL4 when compared to cells exposed to fibroblast exosomes. GSC-secreted exosomes contained distinct protein composition in contrast to fibroblast-secreted exosomes that may affect the anti-tumor function of monocyte-derived macrophages. CONCLUSIONS: Monocytes demonstrated a preferential uptake of GSC-secreted exosomes which then induced a glioma-supportive M2 phenotype. GSC-secreted exosomes can be a contributing factor in the M2 skewing within glioma microenvironment.

Tmic-09glioblastoma stem cell-derived exosomes promote m2 polarization of human monocytes

Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14+ cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1412909

Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes

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Tmic-09glioblastoma stem cell-derived exosomes promote m2 polarization of human monocytes

Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes