Regulatory Role of Immune Cell-Derived Extracellular Vesicles in Cancer: The Message Is in the Envelope
TL;DR: This review focuses on the biological properties of immune cell-derived sEVs, including composition and cellular targeting and mechanisms by which these immune cell -derived s EVs influence tumor immunity either by suppressing or promoting tumor growth.
Abstract: Extracellular vesicles (EVs) are a heterogenous group of membrane-surrounded structures. Besides serving as a harbor for the unwanted material exocytosed by cells, EVs play a critical role in conveying intact protein, genetic, and lipid contents that are important for intercellular communication. EVs, broadly comprised of microvesicles and exosomes, are released to the extracellular environment from nearly all cells either via shedding from the plasma membrane or by originating from the endosomal system. Exosomes are 40-150 nm, endosome-derived small EVs (sEVs) that are released by cells into the extracellular environment. This review focuses on the biological properties of immune cell-derived sEVs, including composition and cellular targeting and mechanisms by which these immune cell-derived sEVs influence tumor immunity either by suppressing or promoting tumor growth, are discussed. The final section of this review discusses how the biological properties of immune cell-derived sEVs can be manipulated to improve their immunogenicity.
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TL;DR: It is shown that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation, and that the continuous activation of Gi- coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release.
Abstract: During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.
194 citations
TL;DR: The role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation are discussed and the mechanism and clinical application prospects of exOSome-based immunotherapy in human cancer are summarized.
Abstract: In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.
179 citations
Cites background from "Regulatory Role of Immune Cell-Deri..."
...In particular, there are still some difficulties in the separation, production, biocompatibility and manufacturing practices of exosomes before clinical realization of their full potential [181, 182]....
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TL;DR: In this paper, the authors highlight several characteristics of γδ T cells and their interactions in leukemia and explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of these lymphocytes against the tumor.
Abstract: Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.
11 citations
TL;DR: In this paper, the role of exosomes in the early diagnosis and treatment of auto-immune thyroid diseases (AITDs) is discussed, aiming to provide new research strategies and directions for early diagnosis of AITDs.
Abstract: Autoimmune thyroid diseases (AITDs) are the most common organ-specific autoimmune diseases, including Hashimoto's thyroiditis (HT) and Graves' disease (GD). The pathogenesis of AITDs has not been fully elucidated. Exosomes are extracellular micro-vesicles (30-150nm) released from cells that contain proteins, lipids, RNA and DNA. They can deliver bioactive molecules and serve as carrier facilitating cell-cell communication, such as antigen presentation, inflammatory activation, autoimmune diseases (AIDs) and tumor metastasis. Research on exosomes in AIDs has attracted much attention, and some studies have shown that exosomes are involved in the occurrence and development of AITDs, but they are still in the preliminary stage of exploration. This review mainly introduces the role of exosomes in AITDs, aiming to provide new research strategies and directions for the early diagnosis and treatment of AITDs.
10 citations
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TL;DR: It is shown that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location, and it is proposed that this RNA is called “exosomal shuttle RNA” (esRNA).
Abstract: Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
10,484 citations
"Regulatory Role of Immune Cell-Deri..." refers background in this paper
...However, significant questions pertaining to sEVs’ potential use as an immune-prophylactic agent or therapeutic for cancer treatment remain unanswered: (1) What is the precise mechanism of action? (2) Which specific cancers are sensitive to this therapeutic strategy? (3) Which membrane vesicle characteristics define immunostimulatory or immunosuppressive properties of sEVs? (4) Can sEV-mediated immunostimulatory effects be reproduced with different batches of sEV preparations? and (5) Can the stimulatory potential...
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...One such class of characterization parameters include: (1) Size of EVs—small EVs (100–200 nm), large EVs (200– 1,000 nm); (2) Sedimentation or density of EVs—low, middle, or high; (3) Marker expression—e.g., CD63, CD81, or Annexin A1expressing EVs; (4) Types of cells—e.g., EVs-derived from heatstressed cells, immune cells, apoptotic cells or hypoxic tumor cells; and (5) Biogenesis—e.g., plasma membrane or endosome....
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...Immune cell-derived sEVs can either activate or suppress the immune responses and these contrasting outcomes are dictated by (1) composition of the cargo, (2) activation and maturation status of the immune cells, (3) identity of target cells, and (4) disease setting and host microenvironment....
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...Importantly, EVs can transfer proteins, mRNA, and microRNA, thus, facilitating the genetic exchange between cells (4)....
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...Tregs exert their immunosuppressive activity through several mechanisms: (1) Tregs consume excess amounts of IL-2, thereby limiting the availability of this cytokine to effector T cells (195); (2) Tregs suppress APC function through constitutive expression of CTLA4, thereby inhibiting the activation of effector T cells (196, 197); (3) Tregs express immunosuppressive cytokines such as TGF-β, IL-10, and IL-35 (198–201); (4) Tregs are instrumental in the conversion of ATP to the immunomodulatory metabolite adenosine which prevents T cell activation (202); and (5) they secrete granzyme and perforin to destroy effector cells (203)....
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TL;DR: Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells and retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+.
Abstract: Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naive T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.
8,082 citations
TL;DR: It is reported that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development and function and ectopic expression ofFoxp3 confers suppressor function on peripheral CD4-CD25− T cells.
Abstract: CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here we report that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in Foxp3-mutant scurfy mice and Foxp3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not from a cell-intrinsic defect of CD4+CD25- T cells. CD4+CD25+ regulatory T cells rescue disease development and preferentially expand when transferred into neonatal Foxp3-deficient mice. Furthermore, ectopic expression of Foxp3 confers suppressor function on peripheral CD4+CD25- T cells. Thus, Foxp3 is a critical regulator of CD4+CD25+ regulatory T cell development and function.
7,321 citations
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
"Regulatory Role of Immune Cell-Deri..." refers background in this paper
...Additionally, the ISEV documented the “Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines” (15); additional findings have led to more recent updates to these guidelines (14)....
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...In 2018, the International Society on Extracellular Vesicles (ISEV) endorsed EV as the generic term to be used for particles of any cellular origin that lack a nucleus and are delimited by a lipid bilayer (14)....
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TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
5,396 citations