Immune Checkpoints

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Regulation of immunity by immune checkpoints

T-cell activation is an important part of effectuating the immune system. A three signal hypothesis has been constructed to explain the mechanism of activation. A first signal is antigen-specific  and is provided through the interaction of the T-Cell receptor with the peptide MHC molecules on the dendritic cell (DC)/ antigen presenting cell (APC) or tumor cell. T cell receptor (TCR) signaling intensity is determined by several factors as antigen load, duration of interaction, MHC molecules, etc.
T cells require also a second signal to become fully activated, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the presenting cell (dendritic-, antigen-presenting-, tumor-cell, etc.) and the T cell., in the absence of this co-stimulatory signal T cells show an absence or diminished reaction when presented with signal 1.
A balanced immune system (maintaining homeostasis) depends on these co-stimulatory signals and is critical for good health. Uncontrolled reactions to antigens or self-antigens could result in auto-immune diseases, or (chronic) inflammation leading to damage in many body tissues. The balance in the immune system is regulated by an equilibrium between co-activating and co-inhibitory stimulatory signals.
These signals that are essential for a homeostasis and good health are also referred to as immune checkpoints. These immune checkpoints and the downstream signaling routes are researched and investigated as a target for the treatment of cancer and other diseases. Small molecules and other biological products that modulate these pathways can help influence the immune response in a manner that alleviates disease.

The last signal also influencing the activation of the T Cells are cytokines. Cytokines produced in the environment of the T cell also influence the genetic programming and the transcription factors. The first 2 described signals are also having an influence on the receptiveness to specific cytokines.

Coming back to the immune checkpoints and the second signal to activate T cells. This is one of the most promising routes to influence antitumor immunity.  Tumors use certain immune checkpoint pathways as a mechanism of immune resistance, particularly against T cells that possess specificity for tumor antigens. The immune checkpoint pathways are activated by ligand–receptor interactions, and can be blocked/neutralized  by antibodies or influenced by adding recombinant ligands or receptors.

The immune checkpoints can be grouped in several families: One of the most intense studied families is the B7-CD28 superfamily​. The B7-family consists of structurally related cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. The co-activating or co-inhibitory signals are delivered through the CD28 family of receptors present on lymphocytes. The binding also influences the production of interleukins. Interaction of B7-family members with co-activating receptors increases immune responses and interaction with co-inhibitory receptors attenuates immune responses.
There are currently several known members of the B7 family: B7-1 (CD80), B7-2 (CD86), inducible costimulator ligand (ICOS-L, B7-H2), programmed death-1 ligand (PD-L1, B7-H1), programmed death-2 ligand (PD-L2, B7-DC), B7-H3, B7-H4, VISTA (B7-H5), B7-H6 and B7-H7. The CD28-superfamily consists of the corresponding receptors to the B7-group of products. The following members are known in this family:CD28, CTLA-4 (CD152), ICOS, PD-1, NKp30, CD28H and BTLA.
Other known immune checkpoint families are the TNF-superfamily and the Immunoglobulin superfamily. There are also a group of receptors and ligands that show immune checkpoint activity but are not part of one of the described families.

B7-CD28 superfamily 

 

Immunoglobulin superfamily

 
Receptor.Alt.nameLigandAlt.nameRegulation
CTLA-4CD152CD80B7-1inhibition
CD28
CD80B7-1activation
CTLA-4
CD86B7-2inhibition
CD28
CD86B7-2activation
PD-1CD279PD-L1B7-H1, CD274inhibition
PD-1CD279PD-L2B7-DC, CD273inhibition
ICOSCD278ICOSLGB7-H2, CD275inhibition
???
CD276B7-H3inhibition
BTLACD272VTCN1B7-H4???
CD28HTMIGD2VISTAB7-H5activation
CD28HTMIGD2HHLA2B7-H7activation
NKp30CD337NCR3LG1B7-H6activation
  
Receptor.Alt.nameLigandAlt.nameRegulation
TIGITVstm3, WUCAMCD155PVRinhibition
TIGITVstm3, WUCAMCD112Nectin-2inhibition
LAG-3
MHC II
inhibition
TIM-3
GAL9
inhibition
SIRP-alpha
CD47
inhibition
KIRCD158MHC II
inhibition
DNAM1CD226CD155PVRactivation
CD96
CD155PVRinhibition
CD96
CD112Nectin-2activation
HVEM*TNFRSF14*CD160BY55, NK1, NK28inhibition
CD2442B4CD48BCM1, BLAST, BLAST1activation
CEACAM1BGP1, BGPICEACAM1BGP1, BGPIinhibition
CD200R
CD200
inhibition
CD112R
CD112Nectin-2inhibition
   *part of TNF-Superfamily

TNF-superfamily

 

Other

 
Receptor. Alt.name Ligand Alt.name Regulation
OX40TNFRSF4OX40LTNFSF4inhibition
4-1BBTNFRSF9, CD1374-1BBLTNFSF9, CD137LGactivation
GITRTNFRSF18, CD357GITRLTNFSF18inhibition
CD27TNFRSF7CD70TNFSF7, CD27LGactivation
CD40TNFRSF5CD40LTNFSF5, CD40LG, CD154inhibition
CD30TNFRSF8CD30LTNFSF8inhibition
DR3TNFRSF25TL1ATNFSF15inhibition
HVEMTNFRSF14LIGHTTNFSF14inhibition
HVEMTNFRSF14BTLA*CD272*???
  
Receptor.Alt.nameLigandAlt.nameRegulation
ADORA2Aadenosine A2a receptor
Adenosine
inhibition


IDO1
inhibition


TDO
inhibition


*part of CD28-Superfamily
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More detailed information on the different members of the B7-CD28 superfamily

Name Information
CD80 (B7-1)CD80 is expressed by activated B cells and by monocytes and dendritic cells. This ligand binds to CD28 to provide a co-stimulatory signal necessary for T cell activation and survival, and cytokine production. Additionally, CD80 binds to CTLA-4 which inhibits T cells.
CD86 (B7-2)CD86 is expressed by activated T and B cells, macrophages, and dendritic cells. This ligand binds to CD28 to provide a co-stimulatory signal necessary for T cell activation and survival, and cytokine production. Additionally, CD80 binds to CTLA-4 which inhibits T cells.
CD28This molecule is constitutively expressed on almost all human CD4+ T-cells and about half of all CD8 T-cells. CD28 binding with two ligands CD80 and CD86, expressed on dendritic cells, the binding results in T cell expansion.
CTLA-4 (CD152)CTLA-4 is expressed on activated T and B lymphocytes. CTLA-4 is structurally similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to the B7 family members B7-1 (CD80) and B7-2 (CD86). Upon ligand binding, CTLA-4 inhibits cell-mediated immune responses. CTLA-4 plays roles in induction and/or maintenance of immunological tolerance, thymocyte development, and regulation of protective immunity. CTLA-4 is part of a group of inhibitory receptors that are explored as cancer treatment targets through immune checkpoint blockade.
PD-L2 (B7-DC)PD-L2 is a transmembrane protein expressed on monocytes, macrophages, and subsets of dendritic cells. PD-L2 binds to its receptor, PD-1, found on CD4 and CD8 thymocytes as well as activated T and B lymphocytes and myeloid cells. Engagement of PD-L2 with PD-1 leads to inhibition of TCR-mediated T cell proliferation and cytokine production.
PD-L1 (B7-H1)PD-L1 is expressed on T lymphocytes, B lymphocytes, NK cells, dendritic cells, as well as IFNγ stimulated monocytes, epithelial cells, and endothelial cells. PD-L1 binds to its receptor, PD-1, found on CD4 and CD8 thymocytes as well as activated T and B lymphocytes and myeloid cells. Engagement of PD-L1 with PD-1 leads to inhibition of TCR-mediated T cell proliferation and cytokine production. PD-L1 is thought to play an important role in circumventing the immune system. Induced PD-L1 expression is common in many tumors and results in increased resistance of tumor cells to CD8 T cell-mediated lysis.
PD-1 (CD279)PD-1 is temporary expressed on CD4 and CD8 thymocytes as well as activated T and B lymphocytes and myeloid cells. PD-1 expression declines after successful elimination of an antigen. PD-1 signals after binding to one of the two ligands, PD-L1 and PD-L2 both members of the B7 family. Upon ligand binding, PD-1 signaling inhibits T-cell activation, leading to reduced proliferation, cytokine production, and T-cell death. Additionally, PD-1 is known to play key roles in tolerance and prevention of autoimmune disease in mice. Induced PD-L1 expression is common in many tumors including squamous cell carcinoma, colon adenocarcinoma, and breast adenocarcinoma. PD-L1 overexpression results in increased resistance of tumor cells to CD8 T cell-mediated lysis. In mouse models of melanoma, tumor growth can be temporarily arrested via treatment with antibodies which block the interaction between PD-L1 and its receptor PD-1. For these reasons anti-PD-1 mediated immunotherapies are currently being explored as cancer treatments.
ICOSLG (CD275,B7-H2)Expressed mainly on B cells and dendritic cells
ICOS (CD278)This molecule, short for Inducible T-cell costimulator, and also called CD278, is expressed on activated T cells. Its ligand is ICOSL, expressed mainly on B cells and dendritic cells. The molecule seems to be important in T cell effector function.
CD276 (B7-H3)CD276 is expressed weakly on activated lymphocytes, macrophages, dendritic cells, nasal and airway epithelial cells, osteoblasts, and some tumor cell lines. A soluble form of CD276 is also secreted by monocytes, dendritic cells, and activated T cells. The biological role of CD276 is still under investigation however, recent studies suggest a negative regulatory role for CD276 in T cell responses.
B7-H4 (VTCN1)B7-H4 is expressed by tumor cells and tumor-associated macrophages and plays a role in tumor escape.
BTLA (CD272)BTLA , short for B and T Lymphocyte Attenuator , has HVEM (Herpesvirus Entry Mediator) as its ligand. Surface expression of BTLA is gradually down regulated during differentiation of human CD8+ T cells from the naive to the effector cell phenotype, however tumor-specific human CD8+ T cells express high levels of BTLA.
VISTA (B7-H5)VISTA - Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on hematopoietic cells. Therefore a consistent expression of VISTA on leukocytes within tumors may allow VISTA blockade to be effective across a broad range of solid tumors.
B7-H6B7-H6 belongs to the B7 family and is selectively expressed on tumor cells. Interaction of B7-H6 with NKp30 (CD337) results in natural killer (NK) cell activation and cytotoxicity.
NKp30 (CD337)Cytotoxicity-activating receptor that contributes to the increased efficiency of activated NK cells to mediate tumor cell lysis
B7-H7B7-H7 is a protein ligand found on the surface of monocytes. The encoded protein is thought to regulate cell-mediated immunity by binding to a receptor on T lymphocytes and inhibiting the proliferation of these cells.
CD28H (TMIGD2)Broad expression in lymph node, spleen, appendix and small intestine also present in 12 other tissues. TMIGD2 is widely expressed on naïve T cells as well as dendritic cells, monocytes, and B cells.


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