Immune checkpoints, molecules in the immune system, are regulators of immune activation by regulating the antigen recognition of T cell receptor (TCR) in the process of immune response. They play a key role in maintaining immune homeostasis and preventing autoimmunity. According to the different role for immune activation, immune checkpoints are divided into two types: co-stimulatory immune checkpoints (turning up a signal) and co-inhibitory immune checkpoints (turning down a signal). Co-stimulatory immune checkpoints refer to one kind of immune checkpoint which can stimulate immune progress, such as CD28, ICOS, and CD137. On the contract, co-inhibitory immune checkpoints play a negative role to immune progress. They inhibit immune progress, such as PD1, CTLA-4, and VISTA.
Generally speaking, the so-called immune checkpoints mainly refer to inhibitory receptors, expressed on T cells or a part of white blood cells. These immune checkpoints primarily play a role in the T cell activation phase. It is gradually being recognized and implemented in clinical that using immunological checkpoint blockade therapy activates T cell and enhance the anti-tumor response of the body's immune system. These inhibitory receptors up-regulate the level of activated T cells in a short time after activation, but long-term sustained stimulation of T cells depletes the potential of T cells, causing T cells to fall into a "exhausted" state. Compared with normal T cells, this T cell proliferative ability is reduced, cytokine production and effector function are weakened, so this T cell can't perform normal immune function to eliminate cancer cells. Studies have shown that blocking these inhibitory receptors can partially reverse T cell failure and increase anti-tumor T cell responses.
The two major precursors in the immune checkpoint are CTLA-4 receptor pathway and PD mediated by CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (cytotoxic T lymphocyte-associated antigen-4) receptor pathway. As it is shown in the following picture:
Fig.1. "Checkpoint" proteins block T-cell activity.
Inhibitor drugs can release the brakes on T cells at different stages
The CTLA-4 checkpoint protein prevents dendritic cells from priming T cells to recognize tumours. Inhibitor drugs block the checkpoint.
The PD-1 checkpoint protein prevents T cells from attacking cancer cell. The inhibitor drug allows T cells to act.
Many cancers protect themselves from the immune system by inhibiting the T cell signal. Currently approved checkpoint inhibitors block CTLA4 and PD-1 and PD-L1. For the related basic science discoveries, James P. Allison and Tasuku Honjo won the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018. So far, the latest research progress of the immune checkpoint has been integrated, and a sweet guy from CUSABIO listed the hot targets of the research. You can click here to view the full targets.