Immune checkpoints are molecules involved in modulating the immune response. They are essential in maintaining self-tolerance and prevent autoimmunity. They act as costimulatory signals in the interaction of antigen-MHC complexes with T cell receptor (TCR). Immune checkpoints are required for the activation of naïve T cells. Checkpoints proteins can be:
Immune checkpoints that inhibit the progression of immune response. Examples of checkpoint inhibitors include Programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and V-domain Ig-containing Suppressor of T cell Activation protein (VISTA).
Immune checkpoint proteins that stimulate immune progress. Examples of stimulatory checkpoints include Cluster of Differentiation 28 (CD28), Inducible T-cell costimulatory protein (ICOS), and Cluster of Differentiation 137 (CD137).
The extend and the duration of immune response depends on the balance between the inhibitory and stimulatory effect of immune checkpoints. They are essential to minimize collateral tissue damage. They are often over-expressed in tumor cells. As a result, blocking immune checkpoints has been considered as a potential approach for antitumor treatment and therapy.
How do Immune checkpoint protein work?
Immune checkpoint are membrane proteins that are initially expressed in endoplasmic reticulum (ER). From ER these proteins are transported to Golgi apparatus where they undergo glycosylation. They are then transported to the cell surface via the secretory vesicles. Once at the cell membrane, these proteins are subject to internalization and recycling. Immune checkpoints cans also undergo ubiquitination-mediated protein degradation. These cellular processes determine the levels of immune checkpoints on the cell surface. The function of immune checkpoints depends on ligand-induced signaling. There are six main signaling mechanism based on ligand-checkpoint interaction.
Immune Checkpoints and Immunotherapy
Immune checkpoints have been essential in cancer immunotherapy. Cancer cells dysregulate immune checkpoint signaling which impairs the immune response. Immunotherapy is a form of cancer treatment that enables immune system to stop or slow the growth of cancer cells. Immunotherapy drugs that target immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the inhibitory signal from being sent which, in turn, enables T cells to kill cancer cells. CTLA-4 and PD1 checkpoint inhibitors have already been approved for cancer therapy with effective efficacy.