Abstract
The programmed cell death 1 (PD-1) pathway is an important regulator of immune responses in peripheral tissues, including abnormal situations such as the tumor microenvironment. This pathway is currently the principal target for immunotherapeutic compounds designed to block immune checkpoint pathways, with these drugs improving clinical outcomes in a number of solid and hematological tumors. Medical oncology is experiencing an immune revolution that has scientists and clinicians looking at alternative, non-redundant inhibitory pathways also involved in regulating immune responses in cancer. A variety of targets have emerged for combinatorial approaches in immune checkpoint blockade. The main purpose of this narrative review is to summarize the biological role of lymphocyte activation gene 3 (LAG3), an emerging targetable inhibitory immune checkpoint molecule. We briefly discuss its role in infection, autoimmune disease and cancer, with a more detailed analysis of current data on LAG3 expression in breast cancer. Current clinical trials testing soluble LAG3 immunoglobulin and LAG3 antagonists are also presented in this work.
Highlights
Improved clinical outcomes have been achieved for a number of solid and hematological diseases treated with immune checkpoint blockade (ICB) targeting cytotoxic T lymphocyte associated protein (CTLA)-4 and programmed cell death 1 (PD-1) or its ligand PD-L1 [1,2,3,4,5,6,7,8,9,10,11]
lymphocyte activation gene 3 (LAG3) functions to control excessive activation following persistent antigen (Ag) exposure in an effort to prevent the onset of autoimmunity [24,25]; it can contribute to a state of T cell dysfunction in the tumor microenvironment (TME) [24,26,27]
The aim of this review is to provide an overview of LAG3 biology under physiological and breast cancer (BC)
Summary
Improved clinical outcomes have been achieved for a number of solid and hematological diseases treated with immune checkpoint blockade (ICB) targeting cytotoxic T lymphocyte associated protein (CTLA)-4 and programmed cell death 1 (PD-1) or its ligand PD-L1 [1,2,3,4,5,6,7,8,9,10,11]. While initial ICB targets have led to an immunological resurgence in oncology, this lack of widespread clinical benefit together with the occurrence of immune related adverse events (irAEs), principally due to the onset of autoimmune reactions [12,13,14,15,16,17], have focused attention on alternative inhibitory immune checkpoint molecules, including lymphocyte activation gene 3 (LAG3, CD223), T cell immunoglobulin mucin 3. The aim ofor this review settings, including autoimmune diseases and tumors LAG3 biology under physiological andmany pathological conditions associated targetingofLAG3 are available in the clinic with more under development with[28]. We include an overview of ongoing early phase clinical trials pathological conditions associated with chronic inflammatory microenvironments, such astargeting that observed in various tumors including breast cancer (BC).
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