Mechanisms of action for different checkpoint inhibitors

Abstract

The immune system is composed of a complex network of cells and soluble factors. This network is specialized in detecting dangerous homeostatic alterations. Once a dangerous alteration is detected, the immune network initiates an immune response to re-establish the homeostasis. Co-inhibitory receptors control the activation and the intensity of the adaptive immune response and therefore, they function as immune checkpoints. The activity of the immune checkpoints is crucial to avoid exacerbated immune responses and autoimmunity by induction of T lymphocyte exhaustion. This process is mainly induced by the chronic exposure to the antigen and is characterized by (i) the progressive loss of the production of proinflammatory cytokines such as tumor necrosis factor alpha and interferon gamma, (ii) the loss of the cytotoxic activity, (iii) the decrease in the proliferative potential and (iv) an increase in apoptosis. Exhaustion is a progressive process that can finally lead to the clonal deletion of T lymphocytes with high-affinity T cell receptor (TCR). The T lymphocytes express progressively co-inhibitory receptors such as PD-1, LAG-3, and TIM-3. This process also involves an epigenetic remodeling that marks a point of terminal exhaustion.