Immune checkpoint

Immune checkpoints (IC) are membrane receptors that are expressed by T lymphocytes. They modulate immune reactions both anti-inflammatory and pro-inflammatory.

In this respect, immune checkpoints in:

• anti-inflammatory ICs and
• pro-inflammatory ICs

can be distinguished.

Anti-inflammatory ICs inhibit the immunoreactivity of T lymphocytes, pro-inflammatory ICs increase the immunoreactivity of T lymphocytes. The immune checkpoints are activated by precisely fitting cytokines (ligands), which are presented and released by various other cells (including tumor cells).

Immune checkpoint inhibitors are synthetic molecules (antibodies) that specifically inhibit a certain immune checkpoint. For example, monoclonal antibodies are used in oncology to block anti-inflammatory immune checkpoints and thus counteract tumor invasion. Their use leads to broad-based immune activation and, particularly in combination, has led to impressive therapeutic results in patients with metastatic melanoma. In particular, antibodies against CTLA4 or PD1- or PD-L1 are administered.

The anti-inflammatory immune checkpoints include:

• A2AR: A2AR is the acronym for "Adenosine A2A Receptor", an adenosine receptor that is activated by the purine nucleoside adenosine.
• B7-H3: B7-H3 is an immune checkpoint molecule expressed by some solid tumors. B7-H3 belongs to the B7 superfamily, a group of molecules that co-stimulate and down-regulate the T cell response.
• BTLA: BTLA, abbreviation for "B- and T-lymphocyte associated", also: "B- and T-lymphocyte attenuator", refers to a protein that serves as a receptor in humans that suppresses immunological reactions. BTLA is a ligand for the tumor necrosis factor receptor (TNF-R).
• CTLA-4: CTLA-4 stands for "Cytotoxic T-lymphocyte associated protein 4" and is a member of the extended CD28 / CTLA-4 family. This family of proteins are T-cell regulators.
• IDO: IDO is the acronym for "indoleamine 2,3-dioxygenase", an enzyme that degrades tryptophan to N-formylkynurenine.
• KIR: KIR is the acronym for "killer-cell immunoglobulin-like receptor". The "killer-cell immunoglobulin-like receptors" are receptors that are mainly found in the /en/internal-medicine/kir-141878" title="Kir cell membranes of natural killer cells (NK cells).
• LAG3: LAG3, acronym for "lymphocyte-activation gene 3", also known as CD223, is a protein that is expressed on the surface of various cells and exerts different biological effects on T cell functions.
• PD-1: PD-1, short for "Programmed Death-1", is a membrane receptor (PD-1 receptor) consisting of 268 amino acids. Like CTL-4, PD-1 is a member of the extended CD28 / CTLA-4 family.
• TIM-3: TIM-3, the acronym for "T-cell immunoglobulin and mucin-domain containing-3" is a protein that belongs to a larger structurally related family (TIM family) of receptor proteins. TIM-3 is expressed on the cell surface of interferon-gamma-producing CD4- and CD8-positive cells.
• VISTA: VISTA, the acronym for "V-domain Ig Suppressor of T cell activation", is a transmembrane protein belonging to the immunoglobulin superfamily. There is evidence that VISTA acts both as a ligand and as a receptor on T cells, thus controlling T cell effector functions and significantly influencing the homeostasis of biological tolerance.

Among the proinflammatory (inflammation-increasing) immune checkpoints, 5 representatives belong to the so-called TNF receptor superfamily: CD27, CD40, OX40, GITR and CD137. 2 others, CD28 and ICOS belong to the B7-CD28 superfamily.

• CD27: CD27 belongs to the tumor necrosis factor receptors (TNFR). CD27 is predominantly expressed by naive helper cells (CD45RA+/CD45RO-).
• CD40: CD40, binding of CD40 and CD154 to T cells enables growth and differentiation of B cells.
• OX40: OX40, also classified as CD252, is the ligand for CD134 and is expressed by dendritic cells (DC2s), which in turn influence the differentiation of Th2 cells. OX40 is a costimulatory "immune checkpoint molecule".
• GITR: "GITR", acronym for "glucocorticoid-induced TNFR-related protein" is a costimulatory immune checkpoint molecule. GITR is a member of the tumor necrosis factor receptor superfamily. The protein influences T-cell activation and plays an essential role in the homeostasis of biological tolerance.
• CD137: CD137 is a member of the tumor necrosis factor (TNF) receptor family. CD137 is a costimulatory immune checkpoint molecule and is expressed by activated T cells, by CD8 cells to a greater extent than by CD4 cells.
• CD28: CD28, is a surface protein in T cells and plasma cells, but not in immature B cells. CD4+ cells express the antigen more frequently than CD8+ cells. CD28 is involved as a costimulator in the activation of T cells. It enhances the formation of interleukin-4 and interleukin-10 in T cells upon activation of the T cell receptor with costimulation by CD40L.
• ICOS: ICOS is the acronym for "inducible T-cell costimulator". ICOS refers to a costimulatory molecule that is expressed on activated T cells (follicular T helper cells).

The use of the new immune checkpoint inhibitors can lead to life-threatening side effects. For this reason, close monitoring and detailed information about possible side effects is absolutely essential.

Possible side effects:

- Autoimmune colitis (therapy option with IVIG)

- Autoimmune hepatitis

- arthritis

- pneumonitis

- myocarditis

- nephritis

- pancreatitis

- Endocrinopathy (diabetes mellitus, adrenal insufficiency, hypothyroidism)

- Autoimmune-mediated polyneuropathy, myositis

- Cutaneous: vitiligo, pruritus, alopecia, SJS/TEN