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Adaptive immunity is regulated by different subgroups of T cells to maintain homeostasis
.
Among them, regulatory T cells (regulatory T cells, Treg) negatively regulate immunity by secreting inhibitory cytokines (such as IL-10, TGF-β) and other methods to prevent the body from excessive immune activation
.
Deficiency of Treg function can cause autoimmune diseases, and overactivation of Treg is one of the contributing factors of tumorigenesis
.
The development of targeted Treg antibody drugs is an important direction for the development of anti-tumor drugs
.
Treg and autoimmune diseases and tumors (Document 1) Regulatory T cell phenotype and function According to the developmental location, regulatory T cells can be divided into two subtypes: Natural Tregs (Natural Tregs, nTregs) are produced in the thymus; Induced Tregs (induced Tregs, iTregs) are naive T cells, which are produced when TCR is stimulated or induced by TGF-β
.
The initial Treg expresses the initial T cell marker CD45RA, while the expression of CD25 and FoxP3 is low.
After TCR is stimulated and induced to differentiate into effector Tregs, CD45RA will no longer be expressed, and the expression of CD25 and FoxP3 will be upregulated
.
The proportion of effective Treg in healthy people is low, accounting for about 2-5% of peripheral blood CD4+T cells.
In the tumor microenvironment, the effective Treg can reach 1-50% of CD4+T
.
Treg maintains immune tolerance (Reference 1) The effector Treg cells are composed of high levels of CTLA-4 and CD25
.
Treg cells activated by TCR stimulation down-regulate the expression of CD80/86 on antigen presenting cells (APC) through CTLA-4, thereby reducing the availability of co-stimulatory molecules for self-reactive TConv cells
.
Together with other inhibitory mechanisms, Treg cells can control the fate of self-reactive T cells and establish long-term tolerance
.
In the case of Treg cells down-regulating the expression of CD80/86, Tconv cells with high affinity TCR for self-peptide/MHC undergo apoptosis, Tconv with medium affinity becomes incompetent, and cells with low affinity are in a dormant state as naive Tconv cells
.
Therefore, removing Treg cells can expand these potentially dangerous self-reactive T cells in healthy individuals
.
The mechanism by which Treg inhibits anti-tumor immunity IL-2 binds to the heterotrimeric IL-2R (formed by the combination of CD25 and CD122 and CD132) expressed on Tregs, and has a high affinity, which leads to IL-2 in the tumor microenvironment.
Lack of IL-2 dependent effector T cell dysfunction
.
Treg secretes perforin and granzyme to directly eliminate cytotoxic effector T cells and NK cells
.
Tregs produce immunosuppressive cytokines, including IL-10, IL-35 and TGF-β, to inhibit the activity of dendritic cells and effector T cells
.
IL-10 and TGF-β bind to cognate receptors on regulatory T cells and induce this inhibitory T cell subpopulation activity
.
CD39 converts extracellular ATP into AMP, which is then converted into adenosine by CD73
.
Adenosine binds to the adenosine A2A and A2B receptors expressed on dendritic cells, effector T cells and NK cells, resulting in immunosuppression
.
Adenosine polarizes macrophages to suppress the M2 phenotype of effector T cells
.
Adenosine drives the expansion of bone marrow-derived suppressor cells
.
Myeloid-derived suppressor cells also mediate CD73-driven adenosine production, thereby further suppressing effector T cells
.
CTLA-4 expressed on Tregs binds to CD80 or CD86 expressed on dendritic cells, resulting in suppression of effector T cells and inducing their apoptosis
.
The combination of CTLA-4/CD80 or CD86 also induces IDO to metabolize tryptophan to kynurenine, resulting in the suppression of effector T cells
.
The depletion of tryptophan in the tumor microenvironment can also lead to the failure and dysfunction of effector T cells
.
Treg inhibits tumor immunity (Document 2) Treg antibody drug development The receptors expressed on the surface of Treg cells include tumor necrosis factor receptor (TNFR) superfamily (TNFR2, OX40, GITR, CD27, 4-1BB), G protein coupled receptors (GPCR) superfamily (CCR4, CCR8), immunoglobulin superfamily (ICOS, CD28, CTLA-4) and immune checkpoint superfamily (TIGIT, LAG-3, TIM3, NRP1, PD-1), involved in Treg mediation Other important receptors/enzymes CD25 and CD39 that lead to immunosuppression
.
Agonists of the TNFR superfamily, antagonists of immune checkpoint inhibitors, etc.
, can all enhance the anti-tumor activity of Treg
.
Treg surface receptors (Reference 2) part of the research drug editor concluded that regulatory T cells are an important force for the body to maintain immune homeostasis, but their immunosuppressive function is a negative factor for anti-tumor immunity
.
Therefore, clearing regulatory T cells, or blocking inhibitory immune signal transduction, activating TNFR and other strategies can enhance anti-tumor immunity
.
At present, many antibody drugs, especially bispecific antibody drugs are under development
.
AstraZeneca and Ionis Pharmaceuticals are developing antisense nucleic acid drugs targeting the Treg transcription factor FoxP3
.
References 1.
James B.
Wing et al, Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer, Immunity 50, February 19, 20192.
Sundee Dees et al, Regulatory T Cell targeting in cancer: emerging strategies in immunotherapy, Eur J Immunol.
2021 Feb;51(2):280-291.
The copyright statement welcomes personal forwarding and sharing
.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Bai Aogu" in a prominent position
.
.
Among them, regulatory T cells (regulatory T cells, Treg) negatively regulate immunity by secreting inhibitory cytokines (such as IL-10, TGF-β) and other methods to prevent the body from excessive immune activation
.
Deficiency of Treg function can cause autoimmune diseases, and overactivation of Treg is one of the contributing factors of tumorigenesis
.
The development of targeted Treg antibody drugs is an important direction for the development of anti-tumor drugs
.
Treg and autoimmune diseases and tumors (Document 1) Regulatory T cell phenotype and function According to the developmental location, regulatory T cells can be divided into two subtypes: Natural Tregs (Natural Tregs, nTregs) are produced in the thymus; Induced Tregs (induced Tregs, iTregs) are naive T cells, which are produced when TCR is stimulated or induced by TGF-β
.
The initial Treg expresses the initial T cell marker CD45RA, while the expression of CD25 and FoxP3 is low.
After TCR is stimulated and induced to differentiate into effector Tregs, CD45RA will no longer be expressed, and the expression of CD25 and FoxP3 will be upregulated
.
The proportion of effective Treg in healthy people is low, accounting for about 2-5% of peripheral blood CD4+T cells.
In the tumor microenvironment, the effective Treg can reach 1-50% of CD4+T
.
Treg maintains immune tolerance (Reference 1) The effector Treg cells are composed of high levels of CTLA-4 and CD25
.
Treg cells activated by TCR stimulation down-regulate the expression of CD80/86 on antigen presenting cells (APC) through CTLA-4, thereby reducing the availability of co-stimulatory molecules for self-reactive TConv cells
.
Together with other inhibitory mechanisms, Treg cells can control the fate of self-reactive T cells and establish long-term tolerance
.
In the case of Treg cells down-regulating the expression of CD80/86, Tconv cells with high affinity TCR for self-peptide/MHC undergo apoptosis, Tconv with medium affinity becomes incompetent, and cells with low affinity are in a dormant state as naive Tconv cells
.
Therefore, removing Treg cells can expand these potentially dangerous self-reactive T cells in healthy individuals
.
The mechanism by which Treg inhibits anti-tumor immunity IL-2 binds to the heterotrimeric IL-2R (formed by the combination of CD25 and CD122 and CD132) expressed on Tregs, and has a high affinity, which leads to IL-2 in the tumor microenvironment.
Lack of IL-2 dependent effector T cell dysfunction
.
Treg secretes perforin and granzyme to directly eliminate cytotoxic effector T cells and NK cells
.
Tregs produce immunosuppressive cytokines, including IL-10, IL-35 and TGF-β, to inhibit the activity of dendritic cells and effector T cells
.
IL-10 and TGF-β bind to cognate receptors on regulatory T cells and induce this inhibitory T cell subpopulation activity
.
CD39 converts extracellular ATP into AMP, which is then converted into adenosine by CD73
.
Adenosine binds to the adenosine A2A and A2B receptors expressed on dendritic cells, effector T cells and NK cells, resulting in immunosuppression
.
Adenosine polarizes macrophages to suppress the M2 phenotype of effector T cells
.
Adenosine drives the expansion of bone marrow-derived suppressor cells
.
Myeloid-derived suppressor cells also mediate CD73-driven adenosine production, thereby further suppressing effector T cells
.
CTLA-4 expressed on Tregs binds to CD80 or CD86 expressed on dendritic cells, resulting in suppression of effector T cells and inducing their apoptosis
.
The combination of CTLA-4/CD80 or CD86 also induces IDO to metabolize tryptophan to kynurenine, resulting in the suppression of effector T cells
.
The depletion of tryptophan in the tumor microenvironment can also lead to the failure and dysfunction of effector T cells
.
Treg inhibits tumor immunity (Document 2) Treg antibody drug development The receptors expressed on the surface of Treg cells include tumor necrosis factor receptor (TNFR) superfamily (TNFR2, OX40, GITR, CD27, 4-1BB), G protein coupled receptors (GPCR) superfamily (CCR4, CCR8), immunoglobulin superfamily (ICOS, CD28, CTLA-4) and immune checkpoint superfamily (TIGIT, LAG-3, TIM3, NRP1, PD-1), involved in Treg mediation Other important receptors/enzymes CD25 and CD39 that lead to immunosuppression
.
Agonists of the TNFR superfamily, antagonists of immune checkpoint inhibitors, etc.
, can all enhance the anti-tumor activity of Treg
.
Treg surface receptors (Reference 2) part of the research drug editor concluded that regulatory T cells are an important force for the body to maintain immune homeostasis, but their immunosuppressive function is a negative factor for anti-tumor immunity
.
Therefore, clearing regulatory T cells, or blocking inhibitory immune signal transduction, activating TNFR and other strategies can enhance anti-tumor immunity
.
At present, many antibody drugs, especially bispecific antibody drugs are under development
.
AstraZeneca and Ionis Pharmaceuticals are developing antisense nucleic acid drugs targeting the Treg transcription factor FoxP3
.
References 1.
James B.
Wing et al, Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer, Immunity 50, February 19, 20192.
Sundee Dees et al, Regulatory T Cell targeting in cancer: emerging strategies in immunotherapy, Eur J Immunol.
2021 Feb;51(2):280-291.
The copyright statement welcomes personal forwarding and sharing
.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Bai Aogu" in a prominent position
.
