Figures & data
Table 1 Immune-checkpoint molecules and their inhibitors
Figure 1 Signaling pathways of immune-checkpoint molecules.
Notes: Binding of PD-L1/L2 to PD-1 recruits SHP-2, which inhibits TCR signaling by CD3ζ-chain dephosphorylation. Thus, the signaling cascade leading to T-cell survival, proliferation, and effector function is inhibited. The SHP-2 recruitment is dependent on its ITSM, whereas the ITIM is not needed for this action. Binding of CTLA-4 to CD80/86, in addition to SHP-2 recruitment, engages PP2A, which directly dephosphorylates AKT. The signaling pathways of TIM-3, LAG-3, and BTLA are less known. Binding of TIM-3 to galectin-9 phosphorylates the Y265 intracellular TIM-3 domain. This disrupts the interaction between TIM-3 and Bat-3, which otherwise inactivates the inhibitory effects of TIM-3. The inhibitory effects due to the binding of MHC II to LAG-3 are dependent on the intracellular KIEELE domain of LAG-3. It is suspected that the intracellular ITIM domain of BTLA is necessary for its inhibitory effects after binding to HVEM.
Abbreviations: BTLA, B- and T-lymphocyte attenuator; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HVEM, herpesvirus entry mediator; ITIM, immunoreceptor tyrosine-based inhibition motif; ITSM, immunoreceptor tyrosine-based inhibition motif; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; P13K, phosphoinositide 3-kinase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PIP3, phosphatidylinositol (3,4,5)-trisphosphat; PP2A, protein phosphatase 2A; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin domain 3.
Abbreviations: BTLA, B- and T-lymphocyte attenuator; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HVEM, herpesvirus entry mediator; ITIM, immunoreceptor tyrosine-based inhibition motif; ITSM, immunoreceptor tyrosine-based inhibition motif; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; P13K, phosphoinositide 3-kinase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PIP3, phosphatidylinositol (3,4,5)-trisphosphat; PP2A, protein phosphatase 2A; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin domain 3.
Table 2 Completed clinical trials of molecules used to overcome T-cell exhaustion in patients with cancer