The magnitude and breadth of the body’s immune response is regulated by balancing co-stimulatory signals and inhibitory signals that prevent indiscriminate attack on self-antigens by preventing autoimmune diseases. These signaling pathways are collectively known as immune checkpoints .
Cancer cells have developed resistance by expressing antigens on their surface that the immune system recognizes as endogenous, thus preventing tumor cells from being recognized and neutralized.
The use of antibodies against immune checkpoints has been a breakthrough in cancer immunotherapy . These antibodies, directed at the immune checkpoints, block them, thus allowing the anti-tumor activity of the immune system to be restored.
4-1BB is a transmembrane protein that is expressed on the surface of T lymphocytes, NK cells, dendritic cells, granulocytes, and mast cells. By binding to its 4-1BBL ligand it provides co-stimulatory signals to CD4 + and CD8 + T cells.
Antibodies against anti-4-1BB immune checkpoints induce T-cell mediated anti-tumor immunity.
4-1BBL is a protein that is part of the TNF superfamily, and is expressed on the surface of dendritic cells, macrophages, and activated B and T lymphocytes. The interaction of 4-1BBL with 4-1BB provides co-stimulatory signals to CD4 + and CD8 + T cells.
CD 40 protein is expressed on the surface of antigen presenting cells such as dendritic cells, B cells, macrophages and monocytes, as well as epithelial cells and in a variety of tumors.
By binding to its CD154 ligand, it acts as a co-stimulator for activation of B cells, dendritic cells, monocytes, and other antigen presenting cells.
CD40 agonist monoclonal antibodies activate antigen presenting cells and promote the antitumor response of T cells.
The CD154 protein is expressed on the surface of activated CD4 + T lymphocytes, as well as on platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, CD8 + T lymphocytes, endothelial cells, epithelial cells, and smooth muscle cells. By binding to CD40, it co-stimulates B and T lymphocytes.
Antibodies against anti-CD154 immune checkpoints interrupt the antigen-specific response of T cells.
The CD47 protein is expressed on the surface of B and T lymphocytes, monocytes, platelets, and erythrocytes, as well as on non-hematopoietic cells. CD47 is involved in a multitude of cellular processes including apoptosis, proliferation, adhesion, and migration, and has been found to be overexpressed in a multitude of different tumor cells.
The CD80 protein is mainly expressed in activated B cells. It binds to CD28 to provide the necessary co-stimulatory signal for T cell activation and cytokine production. It also binds to CTLA-4 which inhibits T cells.
The CD86 protein is expressed on the surface of activated B and T cells, macrophages, and dendritic cells. It binds to CD28 to provide the necessary co-stimulatory signal for T cell activation and cytokine production. It also binds to CTLA-4 which inhibits T cells.
The CD276 protein is weakly expressed in lymphocytes, macrophages, dendritic cells, epithelial cells, osteoblasts, and some tumor cell lines. The most recent studies suggest that this protein negatively regulates the response of T cells.
The CTLA-4 protein is expressed on activated B and T lymphocytes. Structurally, it is similar to the CD28 protein, and both bind to the B7 family ligands: B7-1 (CD80) and B7-2 (CD86). Upon binding, CTLA-4 negatively regulates the cellular immune response.
The LAG-3 protein is expressed in activated T lymphocytes, NK cells, and regulatory T cells. Its main ligand is MHC class II, to which it binds to produce a response similar to that of CTLA-4 or PD-1. It also contributes to the suppressive function of regulatory T cells. In contrast to inhibition, LAG-3 has also been shown to promote the immune response by activating antigen presenting cells.
The OX40 protein is expressed on activated CD8 + and CD4 + T cells. Its main function is to regulate the clonal expansion of CD8 + and CD4 + T cells.
In vivo treatment with an OX40 agonist antibody promotes the generation of antigen-specific effector T cells and prevents the induction of T cell tolerance.
The OX40L protein is expressed in activated B cells and in antigen presenting cells. It is the OX40 (CD134) ligand, which regulates the clonal expansion of CD8 + and CD4 + T cells.
The PD-1 protein is transiently expressed in CD4 and CD8 thymocytes as well as in activated B and T lymphocytes and in myeloid cells. PD-1 expression decreases after successful removal of the antigen. PD-1 has two ligands, PD-L1 and PD-L2, both of the B7 family. Upon binding to these ligands, it inhibits T cell activation, reducing proliferation, cytokine production, and T cell death.
Induction of PD-L1 expression is common in various tumors including squamous cell carcinoma, colon adenocarcinoma, or breast adenocarcinoma. This PD-L1 overexpression results in increased resistance of tumor cells to CD8 + T cell mediated lysis.
Antibodies against immune checkpoints that block the interaction between PD-L1 and its PD-1 receptor fight tumor growth in murine melanoma models.
The PD-L1 protein is expressed on the surface of B and T lymphocytes, NK cells, dendritic cells, epithelial cells, and endothelial cells. It binds to its PD-1 receptor (present in CD4 and CD8 thymocytes, activated B and T lymphocytes, and myeloid cells), causing inhibition of TCR-mediated T cell proliferation and cytokine production.
As previously discussed, induction of PD-L1 expression is common in several tumors including squamous cell carcinoma, colon adenocarcinoma, or breast adenocarcinoma. PD-L1 overexpression results in increased resistance of tumor cells to CD8 + T cell mediated lysis.
PD-L2 is a transmembrane protein belonging to the B7 family, which is expressed in monocytes, macrophages, and dendritic cells. It binds to its PD-1 receptor by inhibiting TCR-mediated T cell proliferation and cytokine production.
TIM-1 is a type I cell surface glycoprotein, which is primarily expressed in TH2 cells. It is a stimulatory molecule for the activation of T cells. It is involved in the mediation of the immune response against viruses, allergic reactions, asthma or tolerance to transplants.
The TIM-3 protein is specifically expressed on the surface of Th1 lymphocytes, and is activated by its binding to galectin-9, inducing apoptosis of Th1 cells.
Inhibition of TIM-3 signaling in mice has been shown to exacerbate autoimmune encephalomyelitis, promote IFN-producción production, and induce proliferation of Th1 cells.
TIM-3 mediated signaling is also being studied as a target for cancer immunotherapy, since CD8 + T cells expressing both TIM-3 and PD-1 exhibit greater defects in cell cycle progression and production of effector cytokines compared to cells expressing PD-1 only.
The VISTA protein, also known as PD-1H or B7-H5, is a type I membrane glycoprotein. It is expressed in activated T cells, NK cells, macrophages, dendritic cells, and neutrophils. It works as a negative immunomodulator, suppressing T cell cytokine production.
Blocking the VISTA protein results in delayed tumor growth in animal models with melanoma.