Back to Pathways
Interactive Pathways & Processes
Show Categories

MDSC-Mediated Mechanisms of Immunosuppression

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

MDSC-Mediated Mechanisms of Immunosuppression
ProductsClose
COX2
COX2
ProductsClose
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
PGES1
PGES1
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
PGE2
PGE2
ProductsClose

Amino Acid Depletion
and Production of
Immunosuppressive
Metabolites

Amino Acid Depletion
and Production of
Immunosuppressive
Metabolites

ProductsClose
PGE2
PGE2
ProductsClose
ProductsClose
EP2
EP2
ProductsClose
ProductsClose
EP4
EP4
ProductsClose
ARG1
ARG1

Inhibition of T Cell
Homing to the Lymph Nodes

Inhibition of T Cell
Homing to the Lymph Nodes

ProductsClose
Low L-arginine
Low L-arginine
ProductsClose

S100A8/A9-mediated
MDSC Accumulation

S100A8/A9-mediated
MDSC Accumulation

ProductsClose
L-arginine
L-arginine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
CAT-2B
CAT-2B
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.

Production of PGE2

Production of PGE2

ProductsClose
L-arginine
L-arginine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.

Generation
of ROS
and RNS

Generation
of ROS
and RNS

ProductsClose
Low L-cysteine
Low L-cysteine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.

Direct Engagement of
T Cell Inhibitory and
Apoptosc Receptors

Direct Engagement of
T Cell Inhibitory and
Apoptosc Receptors

ProductsClose
L-cystine
L-cystine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
Xc-
Xc-
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.

Production of Inhibitory Cytokines

Production of Inhibitory Cytokines

ProductsClose
L-cystine
L-cystine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
IDO
IDO
IDO
ProductsClose
IDO
MDSC
MDSC
ProductsClose
Low L-tryptophan
Low L-tryptophan
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
Presence of kynurenine and derivatives
Presence of kynurenine and derivatives
ProductsClose
ARG1
ARG1
ProductsClose
iNOS
iNOS
ProductsClose
NO
NO
ONOO-
ONOO-
NADPH
Oxidase
NADPH
Oxidase
ProductsClose
S100A8
S100A8
ProductsClose
ProductsClose
S100A9
S100A9
ProductsClose
NO Peroxynitrite
NO Peroxynitrite
H2O2
H2O2
ProductsClose
Galectin-9
Galectin-9
ProductsClose
ProductsClose
TIM-3
TIM-3
ProductsClose
ProductsClose
FasL
FasL
ProductsClose
ProductsClose
Fas
Fas
Fas
ProductsClose
Fas
ProductsClose
PD-L1
PD-L1
ProductsClose
ProductsClose
PD-1
PD-1
ProductsClose
ProductsClose
CCL2
CCL2
ProductsClose
ProductsClose
TGF-beta
TGF-beta
ProductsClose

Production of
Extracellular
Adenosine

Production of
Extracellular
Adenosine

ProductsClose
TGF-beta
TGF-beta
ProductsClose
IL-10, TGF-beta
IL-10, TGF-beta
ProductsClose
ADAM17
ADAM17
ProductsClose
ProductsClose
L-Selectin
L-Selectin
ProductsClose
ProductsClose
CD39
CD39
ProductsClose
CD73
CD73
ProductsClose
ATP
ATP
ATP
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
AMP
AMP
AMP
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
ProductsClose
Adenosine
Adenosine
ProductsClose
We currently do not offer products for this molecule

Use our Product Suggestion form to enter a request.

You will be notified once it becomes available.
A2A/2B R
A2A/2B R
A2A R
A2A R
A2A R
A2A R
A2A R
A2A R
A2A R
A2A R
A2A/2B R
A2A/2B R
S100A8/A9
S100A8/A9
ProductsClose
RAGE
RAGE
ProductsClose
S100A8/A9
S100A8/A9
Natural
Killer Cells
Natural
Killer Cells
ProductsClose
Effector
T Cells
Effector
T Cells
ProductsClose
Dendritic Cells
Dendritic Cells
ProductsClose
Tregs
Tregs
ProductsClose
MDSCs
MDSCs
ProductsClose
T Cells
T Cells
ProductsClose
Tregs
Tregs
ProductsClose
Natural Killer Cells
Natural Killer Cells
ProductsClose
T Cells
T Cells
ProductsClose
Effector
T Cells
Effector
T Cells
ProductsClose
M2
Macrophages
M2
Macrophages
ProductsClose
CD8+
T Cells
CD8+
T Cells
ProductsClose
Natural
Killer
Cells
Natural
Killer
Cells
ProductsClose
Effector
T Cells
Effector
T Cells
ProductsClose
Dendritic
Cells
Dendritic
Cells
ProductsClose
Tregs
Tregs
ProductsClose
Naive CD4+
and CD8+
T Cells
Naive CD4+
and CD8+
T Cells
ProductsClose
Tregs
Tregs
ProductsClose
M2
Macrophages
M2
Macrophages
ProductsClose
NKT
Cells
NKT
Cells
ProductsClose
Natural
Killer Cells
Natural
Killer Cells
ProductsClose
Effector
T Cells
Effector
T Cells
ProductsClose
Dendritic
Cells
Dendritic
Cells
ProductsClose
Tumor-derived
Factors
Tumor-derived
Factors
ProductsClose
O2-
O2-
ProductsClose
H20
H20
ProductsClose

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-2 synthesis and IL-2 R expression
Tregs
• Promotes differentiation and accumulation
MDSCs
• Promotes expansion
• ↑ Suppressive activity
ProductsClose

Amino Acid Depletion and Production of Immunosuppressive Metabolites

T Cells
• Loss of TCR-CD3 zeta chain
• Inhibits proliferation and activity
Tregs
• Promotes development
Natural Killer Cells
• Inhibits proliferation and activity
ProductsClose

Generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS)

T Cells
NO
• Inhibits IL-2 signaling
• Inhibits proliferation and migration
Peroxynitrite
• Promotes nitration or nitrosylation of TCR, CD3, CD8, CCL2, and others
• Inhibits activation
• Inhibits intra-tumoral migration
• Induces apoptosis
H2O2
• Loss of TCR-CD3 zeta chain
• Promotes proliferative arrest
• Induces apoptosis
ProductsClose

Direct Engagement of T Cell Inhibitory and Apoptotic Receptors

Effector T Cells
Galectin-9-TIM-3
• Inhibits Th1 responses
• Induces CD8+ and CD4+ T cell apoptosis
Fas L-Fas
• Induces CD8+ and CD4+ T cell apoptosis
PD-L1-PD-1
• Inhibits T cell activation
• Induces T cell cycle arrest, anergy, and apoptosis
ProductsClose

Production of Inhibitory Cytokines

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

Inhibition of T Cell Homing to the Lymph Nodes

Naive CD4+ and CD8+ T Cells
• Down-regulates L-Selectin/CD62L
• Inhibits naive T cell trafficking and activation
ProductsClose

Production of Extracellular Adenosine

Dendritic Cells
• Inhibits IL-12 secretion and maturation
• Promotes the production of immunosuppressive molecules
Effector T Cells
• Inhibits activity
Natural Killer Cells
• Inhibits activity
NKT Cells
• Inhibits activity
M2 Macrophages
• Promotes activation
Tregs
• Promotes differentiation
• Enhances suppression
ProductsClose

S100A8/A9-Mediated Accumulation of MDSCs

MDSCs
• Inhibits myeloid precursor cell differentiation
• Attracts MDSCs to the tumor microenvironment
ProductsClose
MDSC-Mediated Mechanisms of Immunosuppression

Myeloid-derived Suppressor Cell (MDSC)-Mediated Mechanisms of Immunosuppression

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of early myeloid cells that accumulate during chronic inflammation, autoimmunity, infection, and cancer. Under healthy conditions, these precursor cells terminally differentiate into mature dendritic cells, granulocytes, and macrophages, but under pathological conditions, their differentiation is partially blocked, leading to an accumulation of the immature cells. Immature myeloid cell accumulation is of significant interest as these cells (now known as MDSCs) have immunosuppressive properties and are thought to play a key role in inhibition of the anti-tumor immune response. As a result, they are considered to be a major obstacle for cancer immunotherapy.

Amino Acid Depletion and Production of Immunosuppressive Metabolites by MDSCs

MDSCs inhibit the anti-tumor immune response through multiple mechanisms. One mechanism is through the depletion of amino acids and the production of immunosuppressive metabolites. MDSCs produce high levels of intracellular arginase 1 (ARG1), which leads to increased uptake of L-arginine and depletion of this amino acid from the environment. In the presence of low levels of L-arginine, T cells display reduced expression of TCR-CD3 zeta chain and undergo proliferative arrest. Additionally, MDSCs sequester cystine, which limits its availability to be taken up by antigen-presenting cells (APCs) and subsequently reduced and exported as cysteine. Unlike APCs, MDSCs are capable of importing cystine but they fail to export cysteine due to a lack of the ASC transporter. A reduction in cysteine levels is problematic for T cells, which are unable to generate their own cysteine due to the absence of cystathionine gamma-lyase, an enzyme required for the breakdown of cystathionine into cysteine, and the lack of a functional xc- cystine transporter. As a result, T cells rely on other cells to provide cysteine for their survival. Since cysteine is most highly required during T cell activation and subsequent proliferation and differentiation, it is typically provided to T cells by APCs during antigen presentation. In the presence of MDSCs, however, the levels of cystine imported and cysteine produced by APCs is reduced, thereby compromising T cell activation. MDSCs can also inhibit immune cell functions through the degradation of L-tryptophan. MDSCs express indolamine-2,3-dioxygenase (IDO), which catalyzes the initial, rate-limiting step in L-tryptophan degradation by the kynurenine pathway. The degradation of L-tryptophan and the presence of kynurenine and its derivatives inhibit the proliferation and activity of CD4+ and CD8+ T cells and natural killer cells and promote the differentiation of regulatory T cells (Tregs).

Generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) by MDSCs

A second mechanism by which MDSCs inhibit the anti-tumor immune response is by the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hydrogen peroxide, peryoxynitrite, and nitric oxide (NO) are produced by MDSCs through the activities of NADPH oxidase, arginase-1, and iNOS. These molecules have a variety of immunosuppressive effects on T cells. Hydrogen peroxide promotes loss of TCR-CD3 zeta chain expression and promotes T cell proliferative arrest and apoptosis. Nitric oxide inhibits IL-2 signaling and T cell proliferation and migration, and peryoxynitrite promotes T cell apoptosis, along with nitration or nitrosylation of multiple target molecules including TCR, CD3, CD8, and CCL2, which inhibits T cell activation and intra-tumoral migration.

Direct Engagement of T cell Inhibitory and Apoptotic Receptors by MDSCs

MDSCs may also suppress T cell functions through the direct engagement of T cell inhibitory and apoptotic receptors. In some tumors, activated MDSCs express high levels of PD-L1, Fas Ligand (Fas L), and Galectin-9. Interactions of these ligands with their respective T cell expressed receptors, PD-1, Fas/CD95, or Tim-3 has been shown to lead to either T cell exhaustion in the case of PD-L1/PD-1 or T cell apoptosis in the case of Fas L/Fas and Galectin-9/Tim-3.

Production of Inhibitory Cytokines by MDSCs

MDSCs also mediate immunosuppression through the production of IL-10 and TGF-beta 1. Together these cytokines inhibit the activation, differentiation, and proliferation of effector T cells, as well as inhibit cytokine production by these cells. Additionally, IL-10 and TGF-beta 1 promote the expansion of suppressive T cells. TGF-beta 1 induces the expression of FoxP3 in CD4+CD25- conventional T cells to promote a suppressor cell phenotype in these cells, while IL-10 promotes the conversion of activated conventional T cells to IL-10-, TGF-beta 1-secreting Tr1 cells. In addition to its effects on T cells, TGF-beta 1 also down-regulates the expression of NKG2D and NKp30 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 dendritic cell (DC) maturation and migration, co-stimulatory molecule expression and IL-12 production.

MDSC-Mediated Inhibition of T Cell Homing to the Lymph Nodes

MDSCs can also inhibit T cell activation by preventing the homing of naïve T cells to the lymph nodes. MDSCs were found to constitutively express Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), also known as TACE, which is a protease that has been shown to cleave L-Selectin/CD62L, among other targets. L-Selectin/CD62L plays a key role in directing antigen-naïve CD4+ and CD8+ T cells from the blood and lymphatics to the lymph nodes, where they can then become activated. In the presence of MDSCs, L-Selectin/CD62L on naïve T cells is cleaved by ADAM17, thereby preventing their homing and activation.

Production of Extracellular Adenosine by MDSCs

Similar to regulatory T cells (Tregs) and tumor cells themselves, MDSCs have also been shown to 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 has been shown to inhibit the proliferation and functions of effector T cells, natural killer (NK) cells, and natural killer T (NKT) cells, as well as indirectly affecting T cell functions by acting on antigen-presenting cells. Activation of A2a/A2b receptors on dendritic cells (DCs) promotes their production of immunosuppressive molecules and inhibits their production of IL-12 and TNF-alpha, as well as DC maturation. In addition, adenosine stimulates regulatory T cell (Treg) expansion and increases the suppressive activity of these cells.

Production of PGE2 by MDSCs

MDSCs also produce prostaglandin E2 (PGE2) through the up-regulated expression of the PGE2-producing enzymes, COX2 and PGES1. In an autocrine feedback loop, MDSC-produced PGE2 signals through its receptors expressed on the surface of MDSCs, to up-regulate their expression of arginase 1 (ARG1) and increase their suppressive activity. Additionally, PGE2 has been shown to induce MDSC differentiation of bone marrow stem cells, thereby promoting MDSC expansion. Besides its effects on MDSCs themselves, PGE2 has also been shown to inhibit the cytolytic activity of natural killer (NK) cells and the ability of these cells to produce IFN-gamma. It also inhibits the early stages of dendritic cell differentiation, suppresses IL-2 production and responsiveness in T cells, and inhibits NK/Th1/CD8+ T cell-mediated immune responses while promoting Th2/Th17/Treg responses.

S100A8/A9-Mediated Accumulation of MDSCs

MDSCs promote their own accumulation through an S100A8/A9 autocrine feedback loop. MDSCs synthesize and secrete the calcium-binding proteins, S100A8 and S100A9 that bind to carboxylated N-glycans on the receptor for advanced glycation end-products (RAGE) and other glycoproteins receptors expressed on MDSCs. Interactions of S100A8/A9 with these receptors promotes MDSC accumulation and migration. As a result, S100A8/A9 plays a key role in both the generation and recruitment of MDSCs to the tumor microenvironment.

To learn more, explore the following MDSC-related resources:

Myeloid-Derived Suppressor Cells (MDSC) research area page
Cell Markers for Myeloid-Derived Suppressor Cell Subsets
Blog Post – Immunology News: Targeting Myeloid-Derived Suppressor Cells (MDSCs) for Cancer Immunotherapy
Myeloid-Derived Suppressor Cells Brochure

MDSC-Mediated Mechanisms of Immunosuppression background image 1 MDSC-Mediated Mechanisms of Immunosuppression background image 2 MDSC-Mediated Mechanisms of Immunosuppression background image 3 MDSC-Mediated Mechanisms of Immunosuppression background image 4 MDSC-Mediated Mechanisms of Immunosuppression background image 5 MDSC-Mediated Mechanisms of Immunosuppression background image 6 MDSC-Mediated Mechanisms of Immunosuppression background image 7 MDSC-Mediated Mechanisms of Immunosuppression background image 8 MDSC-Mediated Mechanisms of Immunosuppression background image 9