What are Immune Checkpoints

Immune checkpoints are signaling pathways responsible for downregulating the immune response to avoid destruction of endogenous targets, and tempering the peripheral immune response. During typical interaction of T cells with antigens, complex cytokine signaling provides the immune system confirmation of correctly targeting only non-self antigens, thereby preventing a state of auto-immunity. Typically, this Self-Tolerance allows for clearance of foreign antigens or pathogens without mounting a response against host cells. The difficulty in pointing the immune system against targets such as cancer is therefore its endogenous origin. Appearing wholly "self", cancer escapes immune clearance even when marked as a target through immunization. Replete immune recruitment involves appropriate signaling both to and from a multitude of regulators deemed "immune checkpoints". For example, activated T cells release interferon gamma (IFN-γ), a cytokine responsible for upregulation of checkpoints including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death (PD-1). CTLA-4 and PD-1, as shown in the image below, are examples of co-inhibitory checkpoint receptors which downregulate immune function. Conversely, costimulatory checkpoints such as inducible T cell co-stimulator (ICOS) and tumor necrosis factor superfamily, member4 (TNRFSRF4 or OX40) activate immune function. Taken as a whole, these immune checkpoints act to brake or accelerate immunity. In the context of cancer immunotherapy, amplifying co-stimulation and/or decreasing co-inhibition serves to overcome the self-tolerance afforded to cancer as discussed below.

T Cell Inhibition

Immune Checkpoint Inhibitors

Thanks in part to immune checkpoint inhibitors, the use of the immune system to fight cancer, termed immunotherapy, has seen a resurgence in recent years. Early immunotherapy strategies sought to mount an attack against cancer via vaccine education of the immune system. This alone however proved insufficient, but without obvious rationale. Decades of work has revealed that a possible solution to the stall of this approach lies in the complex signaling involved in T cell activation. Manipulation with immune checkpoint inhibitors removes the restrictions inherent in managing a replete immune response. Mechanistically, blockade of CTLA-4 receptor on the surface of T cells prevents binding to B7 molecules on the surface of antigen presenting cells (APC) or tumor cells. Beyond avoiding the typical inhibition of T cell activation driven by CTLA-4 and B7 binding, B7 is now free to bind to cluster of differentiation 28 (CD28). CD28 is a protein which, when bound to B7, stimulates T cell activation and survival. Similarly, blockade of PD-1 receptor, or it's ligands (PD-L1 or PD-L2), prevents pro-apoptotic signaling and subsequent clearance of T cells. Importantly, these co-inhibitors are active during temporally different stages of the immune response. Checkpoint CTLA-4 is involved during T cell priming in the lymph node and normally prevents T cell proliferation when T cell receptors (TCRs) are strongly stimulated with antigen. PD-1 on the other hand, is involved later in the immune response, acting to dampen inflammatory responses mediated by effector T cells.

Checkpoint Inhibition

Clinical Use of Immune Checkpoint Inhibitors

CTLA-4 and PD-1 have paved the way as both proof of concept for immunomodulation, as well as the first targets to translate into to clinical use. FDA approval for the therapeutic antibody drug ipilimumab (Yervoy®), a CTLA-4 inhibitor, was granted in 2011. PD-1 inhibitor pembrolizumab (Keytruda®) followed shortly after, receiving approval in 2014. With more than a dozen molecules identified to be involved with signaling at the interface of T cells, the discovery of many more therapeutic leads are anticipated. Combination therapy comprised of multiple checkpoint inhibitors, as well as inclusion of checkpoint inhibitors with traditional chemotherapies expand the possibilities even further.

Immune Checkpoint Inhibitors Related Services

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