The emerging role of plasma exosomes in diagnosis, prognosis and therapies of patients with cancer

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Abstract

Exosomes, small (30-150nm) extracellular vesicles of endocytic origin, are present in all body fluids of cancer patients. Tumor-derived exosomes, TEX, emerge as potentially promising non-invasive biomarkers of tumor progression and of immune cell dysfunction in cancer. Exosomes isolated from plasma by size exclusion chromatography can be fractionated into TEX and non-TEX by immune capture on beads. Profiling of molecular and genetic contents of TEX shows that levels if immunosuppressive proteins, such as PD-L1, carried by TEX associate with disease progression. The data suggest that TEX have a to serve as tumor surrogates, while immune cell-derived exosomes might serve as biomarkers of immune dysfunction in cancer.

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Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes.

Douglas Taylor, Sahil Shah (2015)

Viable tumor cells actively release vesicles into the peripheral circulation and other biologic fluids, which exhibit proteins and RNAs characteristic of that cell. Our group demonstrated the presence of these extracellular vesicles of tumor origin within the peripheral circulation of cancer patients and proposed their utility for diagnosing the presence of tumors and monitoring their response to therapy in the 1970s. However, it has only been in the past 10 years that these vesicles have garnered interest based on the recognition that they serve as essential vehicles for intercellular communication, are key determinants of the immunosuppressive microenvironment observed in cancer and provide stability to tumor-derived components that can serve as diagnostic biomarkers. To date, the clinical utility of extracellular vesicles has been hampered by issues with nomenclature and methods of isolation. The term "exosomes" was introduced in 1981 to denote any nanometer-sized vesicles released outside the cell and to differentiate them from intracellular vesicles. Based on this original definition, we use "exosomes" as synonymous with "extracellular vesicles." While our original studies used ultracentrifugation to isolate these vesicles, we immediately became aware of the significant impact of the isolation method on the number, type, content and integrity of the vesicles isolated. In this review, we discuss and compare the most commonly utilized methods for purifying exosomes for post-isolation analyses. The exosomes derived from these approaches have been assessed for quantity and quality of specific RNA populations and specific marker proteins. These results suggest that, while each method purifies exosomal material, there are pros and cons of each and there are critical issues linked with centrifugation-based methods, including co-isolation of non-exosomal materials, damage to the vesicle's membrane structure and non-standardized parameters leading to qualitative and quantitative variability. The down-stream analyses of these resulting varying exosomes can yield misleading results and conclusions.

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Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.

Eva U Wieckowski, Carmen Visus, Marta E Szajnik … (2009)

Sera of patients with cancer contain membraneous microvesicles (MV) able to induce apoptosis of activated T cells by activating the Fas/Fas ligand pathway. However, the cellular origin of MV found in cancer patients' sera varies as do their molecular and cellular profiles. To distinguish tumor-derived MV in cancer patients' sera, we used MAGE 3/6(+) present in tumors and MV. Molecular profiles of MAGE 3/6(+) MV were compared in Western blots or by flow cytometry with those of MV secreted by dendritic cells or activated T cells. These profiles were found to be distinct for each cell type. Only tumor-derived MV were MAGE 3/6(+) and were variably enriched in 42-kDa Fas ligand and MHC class I but not class II molecules. Effects of MV on signaling via the TCR and IL-2R and proliferation or apoptosis of activated primary T cells and T cell subsets were also assessed. Functions of activated CD8(+) and CD4(+) T lymphocytes were differentially modulated by tumor-derived MV. These MV inhibited signaling and proliferation of activated CD8(+) but not CD4(+) T cells and induced apoptosis of CD8(+) T cells, including tumor-reactive, tetramer(+)CD8(+) T cells as detected by flow cytometry for caspase activation and annexin V binding or by DNA fragmentation. Tumor-derived but not dendritic cell-derived MV induced the in vitro expansion of CD4(+)CD25(+)FOXP3(+) T regulatory cells and enhanced their suppressor activity. The data suggest that tumor-derived MV induce immune suppression by promoting T regulatory cell expansion and the demise of antitumor CD8(+) effector T cells, thus contributing to tumor escape.

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Isolation of biologically active and morphologically intact exosomes from plasma of patients with cancer

Chang-Sook Hong, Sonja Funk, Laurent Muller … (2016)

Objective Isolation from human plasma of exosomes that retain functional and morphological integrity for probing their protein, lipid and nucleic acid content is a priority for the future use of exosomes as biomarkers. A method that meets these criteria and can be scaled up for patient monitoring is thus desirable. Methods Plasma specimens (1 mL) of patients with acute myeloid leukaemia (AML) or a head and neck squamous cell carcinoma (HNSCC) were differentially centrifuged, ultrafiltered and fractionated by size exclusion chromatography in small disposable columns (mini-SEC). Exosomes were eluted in phosphate-buffered saline and were evaluated by qNano for particle size and counts, morphology by transmission electron microscopy, protein content, molecular profiles by western blots, and for ability to modify functions of immune cells. Results Exosomes eluting in fractions #3–5 had a diameter ranging from 50 to 200 nm by qNano, with the fraction #4 containing the bulk of clean, unaggregated exosomes. The exosome elution profiles remained constant for repeated runs of the same plasma. Larger plasma volumes could be fractionated running multiple mini-SEC columns in parallel. Particle concentrations per millilitre of plasma in #4 fractions of AML and HNSCC were comparable and were higher (p<0.003) than those in normal controls. Isolated AML exosomes co-incubated with normal human NK cells inhibited NKG2D expression levels (p<0.004), and HNSCC exosomes suppressed activation (p<0.01) and proliferation of activated T lymphocytes (p<0.03). Conclusions Mini-SEC allows for simple and reproducible isolation from human plasma of exosomes retaining structural integrity and functional activity. It enables molecular/functional analysis of the exosome content in serial specimens of human plasma for clinical applications.

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Journal

Journal ID (nlm-ta): Contemp Oncol (Pozn)

Journal ID (iso-abbrev): Contemp Oncol (Pozn)

Journal ID (publisher-id): SWO

Title: Contemporary Oncology

Publisher: Termedia Publishing House

ISSN (Print): 1428-2526

ISSN (Electronic): 1897-4309

Publication date (Electronic): 05 March 2018

Publication date (Print): March 2018

Volume: 22

Issue: 1A

Pages: 38-40

Affiliations

University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, USA

Author notes

Address for correspondence Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA. tel. (412) 624-0096, fax (412) 624-0264. email: whitesidetl@ 123456upmc.edu

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Publisher ID: 31998

DOI: 10.5114/wo.2018.73882

PMC ID: 5885072

PubMed ID: 29628792

SO-VID: f931253a-3a2f-49f7-baab-11d07307eec8

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

The emerging role of plasma exosomes in diagnosis, prognosis and therapies of patients with cancer

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Cancer Immunotherapy

Most cited references 5

Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes.

Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.

Isolation of biologically active and morphologically intact exosomes from plasma of patients with cancer

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