Fig. 1

Mechanisms of action of multiple checkpoints in antitumor immunity. Co-stimulatory and co-inhibitory receptors in the immune synapse. The fine-tuning of the immune response is coordinated by a plethora of co-receptors that are responsible for amplifying or dampening the initial immune response. Most of these receptors require the TCR to specifically recognize antigens displayed by MHC molecules on APCs, to deliver their co-stimulatory or co-inhibitory signals. These interactions can take place either in secondary lymphoid sites where naïve T cells encounter antigen for the first time, or in the periphery where effector cells may be activated or suppressed. Many inhibitory receptors have ITIMs and/or ITSMs in their intracellular domains; however, some receptors have specific motifs, such as UVKM for CTLA-4 and KIEELE for LAG3. The molecular mechanisms of inhibitory receptor signaling are also illustrated and can be divided as ectodomain competition (inhibitory receptors sequester target receptors or ligands); modulation of intracellular mediators (local and transient intracellular attenuation of positive signals from activating receptors, i.e., TCR and co-stimulatory receptors); and induction of inhibitory genes. Multiple inhibitory receptors are responsible for these three mechanisms. Checkpoint therapies with antibodies to T cell inhibitory receptors (e.g., PD-1 and CTLA-4) produce durable responses in patients with many deadly malignancies. Several strategies are used to improve further the success rate of immunotherapies, including (1) combining PD-1 and CTLA-4 blockers with each other or with antagonists of other inhibitory receptors on T cells, such as TIM-3, LAG-3, TIGIT, and BTLA; (2) combining the ICB with agonists of co-stimulatory receptors of T cells, including CD27, 4-1BB, OX40, and GITR; and (3) blocking immune checkpoints in conjunction with stimulation of tumor antigen recognition using vaccines and DC activation by CD40 agonists. An alternative approach involves combining ICBs with other therapies (e.g., radiation, oncolytic viruses) that enhance tumor immunogenicity owing to ICD, and then prompt immune cells recruitment and tumor antigen presentation