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Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression

Click on the mechanisms of tumor-derived exosome (TEX)-mediated immunosuppression listed on the left below under Explore Pathways to see the specific TEX-associated molecules that are involved in each mechanism and an explanation of how they negatively regulate the immune response.

Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression
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MHC I
MHC I
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Latent
TGF-beta
Latent
TGF-beta
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Mature
TGF-beta 1
Mature
TGF-beta 1
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MHC II
MHC II
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Dendritic
Cells
Dendritic
Cells
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T Cells
T Cells
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miRNA
miRNA
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miRNA
miRNA
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miRNA
miRNA
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Mature
TGF-beta 1
Mature
TGF-beta 1
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Mature
TGF-beta 1
Mature
TGF-beta 1
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Natural Killer
Cells
Natural Killer
Cells
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Dendritic
Cells
Dendritic
Cells
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M2
Macrophages
M2
Macrophages
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Stromal Cells
Stromal Cells
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Tregs
Tregs
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PTEN
PTEN
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IL-2 R
IL-2 R
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CD3
TCR-CD3
TCR-CD3
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CD3
IL-2 R
IL-2 R
Jak/STAT
Signaling
Jak/STAT
Signaling
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Natural Killer
Cells
Natural Killer
Cells
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T Cells
T Cells
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Galectin-9
Galectin-9
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TIM-3
TIM-3
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TNF-alpha
TNF-alpha
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TNF RI
TNF RI
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FasL
FasL
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Fas
Fas
Fas
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Fas
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TRAIL
TRAIL
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TRAIL R2
TRAIL R2
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PD-L1
PD-L1
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PD-1
PD-1
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Effector T Cells
Effector T Cells
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MICA/B or
ULBP1-6
MICA/B or
ULBP1-6
Natural Killer
Cells
Natural Killer
Cells
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CD8+
T Cells
CD8+
T Cells
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IL-10
TGF-beta
IL-10
TGF-beta
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Mature
TGF-beta 1
Mature
TGF-beta 1
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TGF-beta 1
TGF-beta 1
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Natural Killer
Cells
Natural Killer
Cells
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CD8+
T Cells
CD8+
T Cells
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Effector
T Cells
Effector
T Cells
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Tregs
Tregs
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Dendritic
Cells
Dendritic
Cells
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M2
Macrophages
M2
Macrophages
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CD39
CD39
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CD73
CD73
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ATP
ATP
ATP
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AMP
AMP
AMP
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Adenosine
Adenosine
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A2AR
A2AR
A2A/2BR
A2A/2BR
A2AR
A2AR
A2AR
A2AR
A2A/2BR
A2A/2BR
A2AR
A2AR
Tregs
Tregs
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M2
Macrophages
M2
Macrophages
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Natural Killer
Cells
Natural Killer
Cells
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NKT
Cells
NKT
Cells
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Dendritic
Cells
Dendritic
Cells
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Effector
T Cells
Effector
T Cells
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Mature
TGF-beta 1
Mature
TGF-beta 1
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PGE2
PGE2
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Natural Killer
Cells
Natural Killer
Cells
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MDSCs
MDSCs
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Dendritic
Cells
Dendritic
Cells
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Tregs
Tregs
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Effector
T Cells
Effector
T Cells
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Tumor-
associated
antigens
Tumor-
associated
antigens
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CD16/Fc gamma RIIIA
CD16/Fc gamma RIIIA
Natural Killer
Cells
Natural Killer
Cells
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Tumor
Cells
Tumor
Cells
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ADCC
ADCC
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mRNAs
mRNAs
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mRNAs
mRNAs
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Oncogenic
Proteins
Oncogenic
Proteins
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Enzymes
Enzymes
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HSPs
HSPs
ds-DNA
ds-DNA
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Tumor-derived Exosome TEX
Tumor-derived Exosome TEX
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Induction of Antigen-
Specific Tolerance

Induction of Antigen-
Specific Tolerance

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miRNA-Induced
Inhibition of Immune
Cell Functions and
Metabolic
Reprogramming of
Stromal Cells

miRNA-Induced
Inhibition of Immune
Cell Functions and
Metabolic
Reprogramming of
Stromal Cells

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Interference with TCR and
IL-2 Signaling

Interference with TCR and
IL-2 Signaling

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Direct Engagement of T Cell
Inhibitory and Apoptotic
Receptors

Direct Engagement of T Cell
Inhibitory and Apoptotic
Receptors

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Expression of Decoy
Natural Killers Cells/
CD8+T Cell Ligands

Expression of Decoy
Natural Killers Cells/
CD8+T Cell Ligands

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Production of Inhibitory
Cytokines

Production of Inhibitory
Cytokines

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Production of Extracellular
Adenosine

Production of Extracellular
Adenosine

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Production of PGE2

Production of PGE2

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Expression of Tumor-
Associated Antigens

Expression of Tumor-
Associated Antigens

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Production of PGE2

Natural Killer Cells
• Inhibits IFN-gamma secretion
• Inhibits cytolytic activity
Effector T Cells
• Inhibits IL-2 synthesis and IL-2 R expression
• Inhibits Th1 differentiation
Dendritic Cells
• Inhibits IL-12 secretion
Tregs
• Promotes differentiation and accumulation
MDSCs
• Promotes expansion
• ↑ Suppressive activity
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Expression of Tumor-Associated Antigens/Antibody Sequestration

• Inhibits antibody-binding to tumor cells
• Inhibits antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells
• Inhibits anti-tumor immunotherapies
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Induction of Antigen-Specific Tolerance

Dendritic Cells
• TEX may be taken up by DCs and inhibit DC maturation and function in the presence of TGF-beta 1.
• TEX may be taken up by DCs which subsequently release tolerogenic, MHC class II+ exosomes that suppress the tumor-specific immune response
T Cells
• May form non-functional MHC-antigen-TCR complexes by down-regulation of CD3 zeta chain expression, leading to inhibition of T cell activation
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miRNA-Induced Inhibition of Immune Cell Functions and Metabolic Reprogramming of Stromal Cells

Natural Killer Cells
• Inhibits activity
Dendritic Cells
• Inhibits MHC II, TLR4, TNF-alpha, IL-12 expression
• Inhibits dendritic cell maturation and Th1 differentiation
• Promotes immune tolerance
M2 Macrophages
• Promotes M2 polarization
Stromal Cells
• Promotes the production of immunosuppressive metabolites
Tregs
• Promotes expansion
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Interference with TCR and IL-2 Signaling

T Cells
• Down-regulation of TCR-CD3 zeta chain and T cell activation
• Inhibition of Jak expression and phosphorylation
• Inhibits IL-2-mediated proliferation and functions
Natural Killer Cells
• Inhibition of Jak expression and phosphorylation
• Inhibits IL-2-mediated proliferation and cytotoxicity
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Direct Engagement of T Cell Inhibitory or Apoptotic Receptors/TEX Incorporation of PTEN

Effector T Cells
Galectin-9-TIM-3
• Inhibits Th1 responses
• Induces CD8+ and CD4+ T cell apoptosis
Fas L-Fas, TNF-alpha-TNF RI, TRAIL-TRAIL R2
• Induces CD8+ and CD4+ T cell apoptosis
PD-L1-PD-1
• Inhibits T cell activation
• Induces T cell cycle arrest, anergy, and apoptosis
PTEN
• Down-regulates Akt phosphorylation
• Decreases expression of anti-apoptotic Bcl family proteins
• Increases expression of pro-apoptotic Bax protein
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Expression of Decoy Natural Killer Cell/CD8+ T Cell Ligands

CD8+ T Cells, Natural Killer Cells
• Down-regulates NKG2D
• Reduces tumor cell recognition
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Production of Inhibitory Cytokines

M2 Macrophages
• Promotes M2 polarization
Dendritic Cells
• Inhibits IL-12 secretion and maturation
• Inhibits co-stimulatory molecule expression
• Promotes the production of immunosuppressive molecules
Tregs
• Promotes expansion
Effector T Cells
• Inhibits activation and differentiation
• Inhibits cytokine production
CD8+ T Cells, Natural Killer Cells
• Down-regulates NKG2D and NKp30
• Inhibits NK cells proliferation and cytotoxicity
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Production of Extracellular Adenosine

Effector T Cells
• Inhibits activity
Dendritic Cells
• Inhibits IL-12 secretion and maturation
• Promotes the production of immunosuppressive molecules
NKT Cells
• Inhibits activity
Natural Killer Cells
• Inhibits activity
M2 Macrophages
• Promotes activation
Tregs
• Promotes differentiation
• Enhances suppression
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Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression

Mechanisms of Tumor-derived Exosome (TEX)-Mediated Immunosuppression

Tumor cells, like most other cells, secrete exosomes, which are small (30-100 nm), membrane-bound extracellular vesicles that are involved in intercellular communication. These vesicles contain both membrane-bound and soluble proteins, lipids, double-stranded DNA, mRNA, and microRNAs (miRNAs) derived from their parent cell. The contents of exosomes may vary, however, depending on the cell type that the exosome originates from, selective sorting of molecules into the exosome, and stress-induced changes in the cellular environment. Following release from its parent cell, an exosome can transfer information to a recipient cell through three possible mechanisms: 1) fusion with the plasma membrane and release of its components into the cytoplasm of the recipient cell, 2) exosome endocytosis through phagocytosis, or 3) receptor-ligand interactions that occur between the exosome and the recipient cell. Once inside the recipient cell, the information obtained from the exosome is functional. Tumor-derived exosomes (TEXs) are abundantly produced in the tumor microenvironment and they carry a variety of immunosuppressive molecules. Interactions between tumor-derived exosomes and immune cells can both directly and indirectly inhibit immune cell functions and the anti-tumor immune response. Due to these properties and the observation that high numbers of tumor-derived exosomes in cancer patients correlate with tumor burden and disease progression, tumor-derived exosomes are now considered to be potential targets for cancer immunotherapy. The mechanisms by which TEXs have been described to mediate immunosuppression are detailed below.

Induction of Antigen-Specific Tolerance by Tumor-derived Exosomes

Tumor-derived exosomes (TEX) carry MHC components, tumor-associated antigens, and other proteins that indicate that they are capable of either immune activation or immunosuppression, but multiple studies suggest TEX promote immunosuppression in the tumor microenvironment. Most studies have demonstrated that the immunosuppressive properties of TEX are primarily antigen-independent, but a few have also suggested that they may suppress anti-tumor immune responses in an antigen-dependent manner as well. In a mouse DTH model, tumor-derived exosomes were shown to be taken up by dendritic cells, inhibit DC maturation and function, and confer antigen-specific immunosuppression. This was associated with increased levels of TGF-beta 1 and IL-4 in the lymph nodes, suggesting that TEX may inhibit tumor antigen-specific immune responses by affecting the functions of antigen-presenting cells (APCs). The presence of TEX has also been shown to be associated with low level expression of co-stimulatory molecules by dendritic cells and the production of inhibitory cytokines, indicating that TEX may condition DCs toward a suppressive or tolerogenic phenotype. An additional study using a subcutaneous tumor model suggested that APCs take up TEX, or tumor-associated antigens from apoptotic tumor cells and subsequently release tolerogenic, MHC class II+ exosomes that suppress tumor-specific immune responses. TEX have also been reported to inhibit CD3 zeta chain expression and it has been further suggested that TEX may impair T cell activation by forming TCR-MHC-peptide complexes with T cells that are unable to properly signal through the TCR.

MicroRNA (miRNA)-Induced Inhibition of Immune Cell Functions and Metabolic Reprogramming of Stromal Cells by Tumor-derived Exosomes

A second mechanism by which tumor-derived exosomes (TEX) inhibit the anti-tumor immune response is through the transfer of microRNAs (miRNAs) to different immune cell types. These miRNAs bind to mRNAs at specific sites and inhibit their translation, which can have negative effects on immune cell functions, depending on the affected mRNAs. Specific miRNAs found in tumor-derived exosomes from pancreatic cancer cells were shown to reduce the expression of MHC class II molecules, TLR4, TNF-alpha, and IL-12 in TEX-pulsed dendritic cells (DCs), which would likely negatively affect the antigen-presentation capabilities of DCs and their abilities to prime T cell activation. Overexpressed miRNAs in TEX from nasopharyngeal cancer were also shown to promote a shift in the T cell-mediated immune response from a Th1/Th17 immune cell phenotype towards a Th2/Treg phenotype. This change in the tumor microenvironment would also suppress the anti-tumor immune response. TEX in some other types of cancers have been shown to carry miRNAs that inhibit the activities of natural killer (NK) cells and monocytes. Additionally, TEX have been demonstrated to metabolically reprogram normal stromal cells to produce metabolites with immunosuppressive properties that support the metabolic needs of the tumor and promote tumor growth.

Interference with TCR and IL-2 Signaling by Tumor-derived Exosomes

Tumor-derived exosomes (TEX) interfere with both T cell receptor (TCR) and IL-2 receptor signaling. TEX disrupt TCR signaling by down-regulating CD3 zeta chain expression, thereby inhibiting T cell activation. TEX have also been shown to reduce the expression and phosphorylation of Janus kinase (Jak) in T cells and natural killer (NK) cells. This is significant as Jak is a critical intracellular kinase involved in mediating signaling by the common cytokine receptor gamma-chain family cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. IL-2, IL-7, and IL-15 in particular, play a critical role in promoting the survival and proliferation of activated T cells and NK cells, as well as NK cell cytotoxicity. As a result, TEX can inhibit both T cell and NK cell proliferation and functions by targeting Jak.

Direct Engagement of T Cell Inhibitory and Apoptotic Receptors by Tumor-derived Exosomes and TEX Incorporation of PTEN

Tumor-derived exosomes (TEX) may also suppress T cell functions through the direct engagement of T cell inhibitory and apoptotic receptors. TEX may express Fas ligand (FasL), TNF-alpha, TRAIL, and Galectin-9, which bind to their respective T cell-expressed receptors, Fas/CD95, TNF RI, TRAIL R2, or Tim-3 and promote T cell apoptosis. Like many tumor cells themselves, TEX may also express high levels of PD-L1. PD-L1 binds to the PD-1 receptor expressed on CD4+ and CD8+ T cells and can inhibit TCR signaling and induce T cell arrest, anergy, and apoptosis. TEX may also express the phosphatase, PTEN, which has been shown to be capable of regulating PI 3-K/Akt activity in CD8+ T cells. Down-regulation of Akt phosphorylation in these cells results in a decrease in the expression of anti-apoptotic Bcl proteins and an up-regulation of pro-apoptotic Bax expression.

Expression of Decoy Natural Killer (NK) Cell/CD8+ T Cell Ligands by Tumor-derived Exosomes

Tumor-derived exosomes (TEX) may directly inhibit natural killer (NK) cells and CD8+ T cells through their expression of membrane-bound NKG2D ligands such as MICA, MICB, or ULBP1-6. These ligands interact with the NKG2D activating receptor expressed on the surface of NK and CD8+ T cells, resulting in prolonged stimulation of these cells. This over-stimulation leads to a down-regulation of NKG2D expression or responsiveness and a decrease in NK cell or CD8+ T cell tumor cell recognition and NK cell cytotoxicity.

Release of Inhibitory Cytokines by Tumor-derived Exosomes

Tumor-derived exosomes also load and release IL-10 and TGF-beta 1, which together inhibit the activation, differentiation, proliferation, and functions of effector T cells, and drive the expansion of T cells with suppressive phenotypes. TGF-beta 1 induces the expression of FoxP3 in CD4+CD25- conventional T cells thereby promoting the expansion of regulatory T cells, while IL-10 promotes the conversion of activated conventional T cells to IL-10-, TGF-beta 1-secreting Tr1 cells. In addition, TGF-beta 1 down-regulates NKG2D and NKp30 expression on natural killer (NK) cells and CD8+ T cells, reduces NK cell proliferation and cytotoxicity, promotes the polarization of macrophages toward a M2 phenotype, and inhibits the expression of co-stimulatory molecules and IL-12 by dendritic cells (DCs), as well as DC maturation and migration.

Production of Extracellular Adenosine by Tumor-derived Exosomes

Tumor-derived exosomes (TEX) from different cancer types also express the surface ectonucleotidases, CD39 and CD73, which work in concert to generate extracellular adenosine from ATP. Extracellular adenosine is an immunosuppressive metabolite that signals through the A2a and A2b receptors expressed on different immune cell types to regulate the activities of these cells and drive tumor escape. Adenosine inhibits the proliferation and functions of natural killer (NK) cells, natural killer T (NKT) cells, and effector T cells, and stimulates regulatory T cell (Treg) expansion as well as Treg suppressive activity. Adenosine also indirectly affects T cell functions by acting on antigen-presenting cells. Activation of A2a/A2b receptors on dendritic cells (DCs) inhibits their production of IL-12 and TNF-alpha, promotes their expression of immunosuppressive molecules, and suppresses DC maturation.

Production of PGE2 by Tumor-derived Exosomes

Another mechanism by which tumor-derived exosomes (TEX) may inhibit the anti-tumor immune response is through the production of prostaglandin E2 (PGE2). PGE2 in the presence of TGF-beta inhibits monocyte differentiation into antigen-presenting dendritic cells, and instead favors the expansion of myeloid-derived suppressor cells (MDSCs) and an increase in their suppressive activity. Additionally, PGE2 has been shown to inhibit the cytolytic activity of natural killer (NK) cells and IFN-gamma production, and to suppress IL-2 production and responsiveness in T cells.

Expression of Tumor-Associated Antigens/Antibody Sequestration

Finally, since tumor-derived exosomes (TEX) carry tumor-associated antigens (TAA), they may condition dendritic cells (DCs) toward a suppressive or tolerogenic phenotype. In addition, TEX may bind and sequester tumor-reactive antibodies, significantly reducing antibody-dependent cellular cytotoxicity (ADCC) mediated by immune effector cells. As this is one of the major mechanisms by which immune cells expressing Fc receptors recognize and destroy antibody-coated cells expressing tumor-associated antigens, TEX may directly promote tumor escape by sequestering antibodies away from tumor cells.

To learn more, explore the following related resources:

Exosomes: Contents by Cell Type and Process Poster

MDSC-Mediated Mechanisms of Immunosuppression Pathway

Mechanisms of Regulatory T Cell-Mediated Suppression Pathway

Mechanisms of Tumor-Associated Macrophage (TAM)-Mediated Immunosuppression

Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 1 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 2 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 3 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 4 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 5 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 6 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 7 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 8 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 9 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 10 Mechanisms of Tumor-derived Exosome (TEX)-mediated Immunosuppression background image 11