Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer

Abstract

Under normal conditions, the immune system responds effectively to both external and internal threats without damaging healthy tissues. Cells undergoing a neoplastic transformation are one such threat. An efficient activation of T cells is enabled by T-cell receptor (TCR) interactions with antigen-presenting class I and class II molecules of the major histocompatibility complex (MHC), co-stimulatory molecules, and cytokines. After threatening stimuli are removed from the body, the host's immune response ceases, which prevents tissue damage or chronic inflammation. The recognition of foreign antigens is highly selective, which requires multistep regulation to avoid reactions against the antigens of healthy cells. This multistep regulation includes central and peripheral tolerance toward the body's own antigens. Here, we discuss T-cell dysfunction, which leads to poor effector function against foreign antigens, including cancer. We describe selected cellular receptors implicated in T-cell dysfunction and discuss how immune-checkpoint inhibitors can help overcome T-cell dysfunction in cancer treatment.

Keywords: B- and T-cell lymphocyte attenuator; T-cell exhaustion; T-cell immunoglobulin and mucin domain 3; checkpoint inhibitors; cytotoxic T-cell antigen 4; lymphocyte-activation gene 3; programmed cell death protein 1.

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.