Programmed cell death protein 1 (PD-1)

The PD-1 receptor (short: PD-1, long: Programmed Cell Death Protein 1) is expressed by immune cells, the T cells. It is a transmembrane protein that binds to its ligands PD-L1 or PD-L2 on tumour cells. This regulates the activity of the T cells.

PD-1 is a member of the immunoglobulin superfamily (IgSF). As with most transmembrane proteins, the receptor can be divided into three parts: the extracellular, transmembrane and intracellular parts.

The extracellular domain of the PD-1 receptor binds to PD-L1 and PD-L2. Binding of the ligands to the receptor causes T-cell activation to be inhibited.

The use of therapeutic monoclonal antibodies (mAbs), e.g. against the programmed cell death protein 1 (PD-1), which are directed against the known immune checkpoints, membrane receptors on the surface of immune cells represent the most important tool of immuno-oncology. Immunotherapeutic approaches against cancer

Modern immunotherapy can be divided into four different approaches:

1. the blockade of the immune checkpoint
2. the cytokine therapy,
3. the cell therapy and
4. therapeutic vaccines

The constant interaction between tumor and immune cells and their importance in the development of cancer is required for understanding the blockage of the immune control point. The aim of the tumor cells is the immune evasion, which means that they want to escape the immune system. For this they have developed complex immunoregulatory mechanisms and are able to suppress the immune responses against them within the tumor microenvironment.

Regulatory T cells (Tregs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and regulatory B cells are responsible for establishing an immunosuppressive microenvironment. To this end, cancer cells release inhibitory cytokines into the tumor microenvironment and express checkpoint inhibitors on their surface to suppress the antitumor activity of specific T cells.

Programmed cell death protein 1 (PD-1)

The programmed cell death protein 1 (PD 1) is expressed on a subgroup of thymocytes and on activated T and B cells and monocytes. PD-1 is an immune receptor and is part of the immunoglobulin superfamily. The ligands for PD-1 are PD-L1 and PD-L2. Both belong to the family of B7 co-stimulatory molecules. They are found on the surface of antigen-presenting cells, endothelial and epithelial cells as well as on activated lymphocytes. The interaction of PD-1 with its PD-L1 and PD-L2 ligands inhibits co-stimulation-induced proliferation and cytokine secretion in T cells. PD-1 acts as an immunomodulatory molecule by down-regulating both T cell and B cell responses.

Monoclonal antibodies against PD-1 / PD-L1

Aim of the immune checkpoint blockade using monoclonal antibodies is the inhibition of intrinsic regulatory mechanisms of the immune system.

PD-1, a membrane receptor for activated T cells, interacts with PD-L1 / 2 to induce inhibition of T cells. Likewise, binding of CTLA-4, another cell membrane receptor on effector T cells, to CD80 / CD86 (B7.1 / 2) on antigen presenting cells (APC) results in suppression of T cell activity. The expression of these receptors on the surface of cancer cells therefore leads to a down-regulated activity of T cells and ultimately to the protection of cancer cells from the immune system. However, an immune checkpoint antibody blocks this immune escape by binding to these receptors and thus enormously supports the immune system in the fight against cancer. In particular, the use of monoclonal anti-PD-1 or anti-PD-L1 antibodies (mab) has led to excellent medical reactions in different cancers.

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