Abstract
The blockade of immune checkpoints (ICPs), such as cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1), has propelled the field of immuno-oncology into its current era. Drugs targeting these ICPs have improved clinical outcome in a number of patients with solid and hematological cancers. Nonetheless, some patients have no benefit from these ICP-blocking therapies. This observation has instigated research into alternative pathways that are responsible for the escape of cancer cells from anti-cancer immune responses. From this research, a number of molecules have emerged as promising therapeutic targets, including lymphocyte activating gene-3 (LAG-3), a next-generation ICP. We will review the current knowledge on the biological activity of LAG-3 and linked herewith its expression on activated immune cells. Moreover, we will discuss the prognostic value of LAG-3 and how LAG-3 expression in tumors can be monitored, which is an aspect that is of utmost importance, as the blockade of LAG-3 is actively pursued in clinical trials.
Highlights
Immune cells are controlled by a plethora of molecules that act as “security brakes”at multiple stages of the immune response
lymphocyte activating gene-3 (LAG-3), called CD223, was identified in 1990 as a receptor that was expressed on a natural killer (NK) cell line cultured with interleukin (IL)-2 [14]
Combinatory treatments that incorporate the blockade of LAG-3 are viewed as a promising approach to improve current immunotherapies
Summary
Immune cells are controlled by a plethora of molecules that act as “security brakes”. These regulations are important to prevent the destruction of tissues caused by inappropriate and/or disproportionate responses to invading pathogens Cancer cells exploit such inhibitory immune checkpoints (ICPs) to escape destructive tumor-specific immune responses, which is unfavorable for the patients’. The list of inhibitory ICPs that negatively regulate anti-tumor immune responses is growing Among these next-generation ICPs, lymphocyte activating gene-3 (LAG-3, CD233) has emerged as an eminent target in the development of cancer treatment and holds substantial prognostic value. Patients are selected for treatment with ICP-blocking mAbs, depending on the level of inhibitory ICP expression in the tumor microenvironment (TME), which is determined using immunohistochemistry (IHC). Some patients with IHC samples that show a clear expression of ICPs in the TME are observed not to react to ICPblocking mAbs [10,11].
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