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Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments

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Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (10 March 2022) | Viewed by 37069

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Special Issue Editors

Prof. Dr. Richard B. Bankert

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Guest Editor

Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA
Interests: tumor microenvironment; immunology; exosome; extracellular vesicles; T cell immunity

Dr. Gautam N. Shenoy

E-Mail Website1 Website2
Guest Editor

Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA
Interests: cancer immunology; immunotherapy; exosomes; tumor microenvironment; T cell immunity; chronic inflammation; immunogenicity of protein therapeutics; oral tolerance

Special Issue Information

Dear Colleagues,

Small extracellular vesicles ranging in size from 30-150 nm and surrounded by a lipid bilayer, known as exosomes, are present in the microenvironment of tumor and chronic inflammatory tissues. These tumor-associated exosomes are heterogeneous and are derived from both normal and neoplastic cells. Exosomes have been reported to serve a plethora of different functions in regulating health and disease, including the progression of tumors and chronic inflammatory conditions such as rheumatoid arthritis and chronic rhinosinusitis by inducing immunosuppression. The immunosuppressive nature of these exosomes has been ascribed to their constituents, which include lipids (e.g. phosphatidylserine, ganglioside GD3), proteins (e.g. PD-L1, IL-10) and nucleic acids (e.g. miR-24-3p). Some of these immunosuppressive molecules have been identified as being present on the surface of exosomes (e.g. phosphatidylserine) while others are part of the exosomal cargo (e.g. IL-10).

The aim of this special issue is to present and review in vitro as well as in vivo data that identify the presence of immunosuppressive exosomes in tumors and chronic inflammatory microenvironments, establish mechanisms of immunosuppression, and explore the viability of strategies for targeting these vesicles as means of therapeutic intervention. We invite original contributions as well as review articles that provide new insights to help us better understand the fascinating world of these nano-sized vesicles.

Prof. Dr. Richard B. Bankert
Dr. Gautam N. Shenoy
Guest Editors

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Keywords

Exosomes
Extracellular vesicles
Tumor microenvironment
Chronic inflammation
T cell responses
Immunosuppression
Therapeutic targets

Published Papers (10 papers)

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Research

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14 pages, 3131 KiB

Open AccessArticle

Evaluation of Immunoregulatory Biomarkers on Plasma Small Extracellular Vesicles for Disease Progression and Early Therapeutic Response in Head and Neck Cancer

by Jadwiga Jablonska, Malwina Rist, Ilona Spyra, Luisa Tengler, Maksim Domnich, Benjamin Kansy, Bernd Giebel, Basant Kumar Thakur, Nicole Rotter, Stephan Lang and Sonja Ludwig

Cells 2022, 11(5), 902; https://doi.org/10.3390/cells11050902 - 5 Mar 2022

Cited by 11 | Viewed by 2594

Abstract

Head and Neck Cancers (HNCs) have highly immunosuppressive properties. Small extracellular vesicles (sEVs), including exosomes, nanosized mediators of intercellular communication in the blood, carry immunosuppressive proteins and effectively inhibit anti-tumor immune responses in HNCs. This study evaluates immunosuppressive markers on sEVs from 40 HNC patients at different disease stages and 3- and 6-month follow-up after surgery and/or chemoradiotherapy. As controls, sEVs from normal donors (NDs) are examined. Immunoregulatory surface markers on sEVs were detected as relative fluorescence intensity (RFI) using on-bead flow cytometry, and their expression levels were monitored in the early and late stages of HNC and during follow-up. In parallel, the sEV-mediated apoptosis of CD8⁺ Jurkat cells was assessed. Together with TGF-β1 and PD-L1 abundance, total sEV proteins are elevated with disease progression. In contrast, total sEV protein, including TGF-β1, PD-1 and PD-L1, decrease upon therapy response during follow-up. Overall survival analysis implies that high sEV PD-1/PD-L1 content is an unfavorable prognostic marker in HNC. Consistently, the sEV-mediated induction of apoptosis in CD8⁺ T cells correlates with the disease activity and therapy response. These findings indicate that a combination of immunoregulatory marker profiles should be preferred over a single marker to monitor disease progression and therapy response in HNC. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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7 pages, 926 KiB

Open AccessArticle

The Role of Tumor-Derived Exosomes (TEX) in Shaping Anti-Tumor Immune Competence

by Theresa L. Whiteside

Cells 2021, 10(11), 3054; https://doi.org/10.3390/cells10113054 - 6 Nov 2021

Cited by 13 | Viewed by 2332

Abstract

Emerging studies suggest that extracellular vesicles (EVs) mediating intercellular communication in the tumor microenvironment (TME) play a key role in driving cancer progression. Tumor-derived small EVs or exosomes (TEX) enriched in immunosuppressive proteins or in microRNAs targeting suppressive pathways in recipient cells contribute to reprogramming the TME into a cancer-promoting milieu. The adenosinergic pathway is an acknowledged major contributor to tumor-induced immune suppression. TEX carry the components of this pathway and utilize ATP to produce adenosine (ADO). TEX-associated ADO emerges as a key factor in the suppression of T cell responses to therapy. Here, the significance of the ADO pathway in TEX is discussed as a highly effective mechanism of cancer-driven immune cell suppression and of resistance to immune therapies. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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Review

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17 pages, 1727 KiB

Open AccessReview

Exosomal Plasma Gelsolin Is an Immunosuppressive Mediator in the Ovarian Tumor Microenvironment and a Determinant of Chemoresistance

by Toshimichi Onuma, Meshach Asare-Werehene, Yoshio Yoshida and Benjamin K. Tsang

Cells 2022, 11(20), 3305; https://doi.org/10.3390/cells11203305 - 20 Oct 2022

Cited by 5 | Viewed by 2276

Abstract

Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance. Overexpression of plasma gelsolin (pGSN) is key contributing factor to OVCA chemoresistance and immunosuppression. Gelsolin (GSN) is a multifunctional protein that regulates the activity of actin filaments by cleavage, capping, and nucleation. Generally, it plays an important role in cytoskeletal remodeling. GSN has three isoforms: cytosolic GSN, plasma GSN (pGSN), and gelsolin-3. Exosomes containing pGSN are released and contribute to the progression of OVCA. This review describes how pGSN overexpression inhibits chemotherapy-induced apoptosis and triggers positive feedback loops of pGSN expression. It also describes the mechanisms by which exosomal pGSN promotes apoptosis and dysfunction in tumor-killing immune cells. A discussion on the potential of pGSN as a prognostic, diagnostic, and therapeutic marker is also presented herein. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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18 pages, 1489 KiB

Open AccessFeature PaperReview

Exosome-Mediated Immunosuppression in Tumor Microenvironments

by Qi-Hui Xie, Ji-Qi Zheng, Jia-Yi Ding, Yu-Fei Wu, Luisa Liu, Zi-Li Yu and Gang Chen

Cells 2022, 11(12), 1946; https://doi.org/10.3390/cells11121946 - 16 Jun 2022

Cited by 41 | Viewed by 5487

Abstract

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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28 pages, 1560 KiB

Open AccessReview

Immunosuppressive Extracellular Vesicles as a Linking Factor in the Development of Tumor and Endometriotic Lesions in the Gynecologic Tract

by Karolina Soroczynska, Lukasz Zareba, Magdalena Dlugolecka and Malgorzata Czystowska-Kuzmicz

Cells 2022, 11(9), 1483; https://doi.org/10.3390/cells11091483 - 28 Apr 2022

Cited by 4 | Viewed by 3214

Abstract

Both gynecological tumors and endometriosis require for their development a favorable environment, termed in the case of tumors a “pre-metastatic niche” and in case of endometriosis a “pro-endometriotic niche”. This is characterized by chronic inflammation and immunosuppression that support the further progression of initial lesions. This microenvironment is established and shaped in the course of a vivid cross-talk between the tumor or endometrial cells with other stromal, endothelial and immune cells. There is emerging evidence that extracellular vesicles (EVs) play a key role in this cellular communication, mediating both in tumors and endometriosis similar immunosuppressive and pro-inflammatory mechanisms. In this review, we discuss the latest findings about EVs as immunosuppressive factors, highlighting the parallels between gynecological tumors and endometriosis. Furthermore, we outline their role as potential diagnostic or prognostic biomarkers as well as their future in therapeutic applications. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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Graphical abstract

17 pages, 1321 KiB

Open AccessReview

The Role of Exosomes in Inflammatory Diseases and Tumor-Related Inflammation

by Yuan Tian, Cheng Cheng, Yuchong Wei, Fang Yang and Guiying Li

Cells 2022, 11(6), 1005; https://doi.org/10.3390/cells11061005 - 16 Mar 2022

Cited by 22 | Viewed by 4187

Abstract

Inflammation plays a decisive role in inducing tumorigenesis, promoting tumor development, tumor invasion and migration. The interaction of cancer cells with their surrounding stromal cells and inflammatory cells further forms an inflammatory tumor microenvironment (TME). The large number of cells present within the TME, such as mesenchymal stem cells (MSCs), macrophages, neutrophils, etc., play different roles in the changing TME. Exosomes, extracellular vesicles released by various types of cells, participate in a variety of inflammatory diseases and tumor-related inflammation. As an important communication medium between cells, exosomes continuously regulate the inflammatory microenvironment. In this review, we focused on the role of exosomes in inflammatory diseases and tumor-related inflammation. In addition, we also summarized the functions of exosomes released by various cells in inflammatory diseases and in the TME during the transformation of inflammatory diseases to tumors. We discussed in depth the potential of exosomes as targets and tools to treat inflammatory diseases and tumor-related inflammation. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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22 pages, 1151 KiB

Open AccessReview

Exogenous and Endogenous Dendritic Cell-Derived Exosomes: Lessons Learned for Immunotherapy and Disease Pathogenesis

by Mahmoud Elashiry, Ranya Elsayed and Christopher W. Cutler

Cells 2022, 11(1), 115; https://doi.org/10.3390/cells11010115 - 30 Dec 2021

Cited by 29 | Viewed by 4009

Abstract

Immune therapeutic exosomes, derived exogenously from dendritic cells (DCs), the ‘directors’ of the immune response, are receiving favorable safety and tolerance profiles in phase I and II clinical trials for a growing number of inflammatory and neoplastic diseases. DC-derived exosomes (EXO), the focus of this review, can be custom tailored with immunoregulatory or immunostimulatory molecules for specific immune cell targeting. Moreover, the relative stability, small size and rapid uptake of EXO by recipient immune cells offer intriguing options for therapeutic purposes. This necessitates an in-depth understanding of mechanisms of EXO biogenesis, uptake and routing by recipient immune cells, as well as their in vivo biodistribution. Against this backdrop is recognition of endogenous exosomes, secreted by all cells, the molecular content of which is reflective of the metabolic state of these cells. In this regard, exosome biogenesis and secretion is regulated by cell stressors of chronic inflammation and tumorigenesis, including dysbiotic microbes, reactive oxygen species and DNA damage. Such cell stressors can promote premature senescence in young cells through the senescence associated secretory phenotype (SASP). Pathological exosomes of the SASP amplify inflammatory signaling in stressed cells in an autocrine fashion or promote inflammatory signaling to normal neighboring cells in paracrine, without the requirement of cell-to-cell contact. In summary, we review relevant lessons learned from the use of exogenous DC exosomes for immune therapy, as well as the pathogenic potential of endogenous DC exosomes. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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13 pages, 968 KiB

Open AccessReview

The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

by Lingxiao Ye, Zhengxin Zhu, Xiaochuan Chen, Haoran Zhang, Jiaqi Huang, Shengxian Gu and Xiaoyin Zhao

Cells 2021, 10(11), 3247; https://doi.org/10.3390/cells10113247 - 19 Nov 2021

Cited by 28 | Viewed by 5002

Abstract

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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18 pages, 1764 KiB

Open AccessReview

Tumor-Associated Exosomes: A Potential Therapeutic Target for Restoring Anti-Tumor T Cell Responses in Human Tumor Microenvironments

by Gautam N. Shenoy, Maulasri Bhatta and Richard B. Bankert

Cells 2021, 10(11), 3155; https://doi.org/10.3390/cells10113155 - 13 Nov 2021

Cited by 11 | Viewed by 3225

Abstract

Exosomes are a subset of extracellular vesicles (EVs) that are released by cells and play a variety of physiological roles including regulation of the immune system. Exosomes are heterogeneous and present in vast numbers in tumor microenvironments. A large subset of these vesicles has been demonstrated to be immunosuppressive. In this review, we focus on the suppression of T cell function by exosomes in human tumor microenvironments. We start with a brief introduction to exosomes, with emphasis on their biogenesis, isolation and characterization. Next, we discuss the immunosuppressive effect of exosomes on T cells, reviewing in vitro studies demonstrating the role of different proteins, nucleic acids and lipids known to be associated with exosome-mediated suppression of T cell function. Here, we also discuss initial proof-of-principle studies that established the potential for rescuing T cell function by blocking or targeting exosomes. In the final section, we review different in vivo models that were utilized to study as well as target exosome-mediated immunosuppression, highlighting the Xenomimetic mouse (X-mouse) model and the Omental Tumor Xenograft (OTX) model that were featured in a recent study to evaluate the efficacy of a novel phosphatidylserine-binding molecule for targeting immunosuppressive tumor-associated exosomes. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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Graphical abstract

17 pages, 1896 KiB

Open AccessFeature PaperReview

Extracellular Vesicles (Exosomes) as Immunosuppressive Mediating Variables in Tumor and Chronic Inflammatory Microenvironments

by Annoor Awadasseid, Yanling Wu and Wen Zhang

Cells 2021, 10(10), 2533; https://doi.org/10.3390/cells10102533 - 24 Sep 2021

Cited by 8 | Viewed by 3275

Abstract

Exosomes are extracellular vesicles released by most of the eukaryotic cells. Exosomes’ components include proteins, lipids, microRNA, circular RNA, long noncoding RNA, DNA, etc. Exosomes may carry both pro and anti-inflammatory cargos; however, exosomes are predominantly filled with immunosuppressive cargos such as enzymes and microRNAs in chronic inflammation. Exosomes have surfaced as essential participants in physiological and pathological intercellular communication. Exosomes may prevent or promote the formation of an aggressive tumor and chronic inflammatory microenvironments, thus influencing tumor and chronic inflammatory progression as well as clinical prognosis. Exosomes, which transmit many signals that may either enhance or constrain immunosuppression of lymphoid and myeloid cell populations in tumors, are increasingly becoming recognized as significant mediators of immune regulation in cancer. In this review, we outline the function of exosomes as mediators of immunosuppression in tumor and chronic inflammatory microenvironments, with the aim to improve cancer therapy. Full article

(This article belongs to the Special Issue Exosomes as Mediators of Immunosuppression in Tumor and Chronic Inflammatory Microenvironments)

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