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Immune responses are regulated by a delicate balance of stimulatory and inhibitory signals that control the activation and functions of different immune cell types. These signals are delivered by receptors known as immune checkpoint molecules. While stimulatory immune checkpoint receptors promote immune cell activation to eliminate invading pathogens and developing malignancies, inhibitory immune checkpoint molecules regulate the magnitude and duration of immune responses by suppressing immune cell activation. Although this balance is necessary to prevent excessive inflammation and restore immune homeostasis under physiological conditions, many tumor cells are capable of exploiting negative regulatory immune checkpoint pathways by inducing or up-regulating the expression of ligands that activate immune cell inhibitory receptors. As a result, they can evade immune detection and elimination. Due to these discoveries, many researchers and clinicians have focused on targeting immune checkpoint molecules for cancer immunotherapy using either antagonists of immune cell inhibitory receptors or agonists of immune cell stimulatory receptors to attempt to restore or amplify immune cell activation.

CD8+ cytotoxic T cells (CTLs) and natural killer cells are two of the key immune cell types involved in detecting and removing cancer cells, and two of the central cell types being targeted by immune checkpoint blockade strategies. This poster shows the current and emerging immune checkpoint molecules expressed on these cells that are being investigated as potential targets for cancer immunotherapy. The left-hand side of the poster shows the co-stimulatory and co-inhibitory receptors that are involved in regulating T cell activation (Signal 2), following T cell receptor (TCR)-mediated recognition of the antigen/major histocompatibility complex (MHC) expressed on antigen-presenting cells (Signal 1). Arrows with the + symbol denote receptors that stimulate T cell activation in response to an infection or developing malignancy, while arrows with the – symbol denote receptors that inhibit T cell activation. The right-hand side of the poster shows the inhibitory immune checkpoint pathways that tumor cells are capable of exploiting to negatively regulate T cell and/or natural killer cell activation. As both T cells and natural killer cells can become dysfunctional or exhausted under conditions of chronic stimulation such as those commonly associated with persistent infections or cancer, the characteristics of exhausted T cells and natural killer cells are also shown. In both cell types, the exhausted state is associated with a decrease in proliferative capacity, impaired effector functions, and up-regulated and sustained expression of multiple inhibitory immune checkpoint receptors. These findings further suggest that inhibitory immune checkpoint blockade may help to restore T cell and natural killer cell functions and reinvigorate anti-tumor immune responses.

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