Fig. 2

Immune checkpoint inhibition pathways in tumors (a) Activation of CTLA-4 pathway: Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA-4 on their surface. Instead, CTLA-4 is sequestered in intracellular vesicles. CTLA-4 is a CD28 homologue with higher affinity for the ligands CD80 (B7–1) or CD86 (B7–2) that it shares with CD28. After the T-cell receptor (TCR) is triggered by an antigen encounter, CTLA-4 is transported to the cell surface. The stronger the stimulation through the TCR and CD28, the greater the amount of CTLA-4 that is expressed on the T-cell surface, resulting in a net negative signal transduced by the CTLA-4: CD80/86 interaction. This mechanism results in CD8⁺T-cell inhibition, despite the presence of widely varying concentrations and affinities of ligand for the TCR. The negative T-cell inhibition or immunosuppressive signal is characterized by decrease in cytokine secretion, CD8⁺T-cell inactivation and loss of its cytotoxic function (b) Activation of PD-1/PD L-1 pathway: PD-1, a member of the B7/CD28 family of co-stimulatory receptors, regulates T-cell activation through binding to its ligands, programmed death ligand 1 (PDL-1) and programmed death ligand 2 (PDL-2). During inflammatory responses in tissues or in the setting of chronic antigen exposure (including tumor antigens), activated T-cells up-regulate PD-1 and continue to express it in tissues. In case of tumors, constitutive tumor signal (tumor antigen and PDL-1 expression) results in overstimulation of CD8⁺T cells and inhibits them by inducing a state of anergy or exhaustion. c During Immune Checkpoint Inhibition therapy, anti CTLA-4, anti-PD-L1 or anti-PD-1 antibodies bind to their corresponding target molecules preventing the receptor-ligand interactions of these immune checkpoint inhibitors. This releases CD8⁺T-cells from immunosuppression imposed on them either by tumor cells via PD-1/PDL-1 pathway or by CTLA-4 pathway, which then resume their anti-oncogenic role