Immune Checkpoints

Immune checkpoints are regulators of the immune system, and thus play an integral role in self-tolerance and antigen recognition of the T cell receptors in the process of immune response – specifically, cancer and other such diseases. As some cancers stimulate immune checkpoint targets, these molecules make important immunotherapy candidates.

T cell activation requires two signals: recognition of the antigenic peptide MHC complex by TCR and the antigen-independent co-stimulation induced by molecules on target cells (such as antigen presenting cells). Immune checkpoint therapy relies on a functioning immune system with agonists of co-stimulatory signals or antagonists of inhibitory signals.

Co-stimulatory and co-inhibitory molecules are cell surface receptors and ligands. After interaction with their specific ligands or counter-receptors, they regulate T cell function and trigger signals in T cells.

CO-STIMULATORY RECEPTORS

These include various checkpoint molecules whose stimulation regulates and increases target cell functions. Some of these stimulatory receptor molecules belong to the TNF receptor super family, and the B7-CD28 superfamily. Primarily, they are involved in prompting T cell activation, differentiation / proliferation and expansion.

CO-INHIBTORY RECEPTORS

Also known as immune checkpoint molecules, these inhibitors supress function of the immune checkpoint pathways, enhancing immunity against cancer. Currently, therapies being developed are blocking antibodies, and they have emerged as a mainstay in several solid tumors and lymphoma etc. Immune checkpoint therapy has elicited robust responses in clinical uses and several new trials are underway for new targets and drugs.

Co-inhibitory pathways include:

• CD47/SIRP alpha pathway
• PD-1/PD-L1 pathway
• TIGIT pathway
• CTLA-4 pathway
• LAG-3 pathway