Lymphocyte activation gene-3 as a candidate target for combo anti-programmed death-(ligand) 1 therapy of cancer

Lymphocyte activation gene-3 (Lag-3, also called CD223) is an immune checkpoint and a cell surface molecule that is overexpressed in several solid cancer types and promotes tolerance to self and tumor-related antigens. Lag3 evaluation in tumor samples can be served as a prognostic biomarker in cancer. This checkpoint is expressed preferentially on tumor-infiltrating lymphocytes (TILs), and its overexpression negatively regulates their effector activity and augments the release of immunosuppressive cytokines into the tumor area. Lag-3 positively and extensively correlates with programmed death-1 (PD-1) expression on TILs, and their combined expression promote CD4+ and CD8+ T cell exhaustion and apoptosis. Exhausted T cells expressing Lag-3 are resistant to antiPD-(L)1, so Lag-3 can be a desired target in dual anti-checkpoint therapy. Targeting Lag-3 represents more power to modify the immune backbone of tumor, and its clinical efficacy is more potent compared with anti-PD-(L)1 therapy. Combo anti-Lag-3/anti-PD-1 can abrogate tolerance among cells of immune system, restore T cell effector function and boost anti-tumor immune responses against cancer in a way more pronounced compared with solo anti-Lag-3 or anti-PD-(L)1, and is particularly effective in anti-PD-(L)1 naive patients. An advance in the field is the development of bispecific antibodies against Lag-3 and PD-(L)1 with a synergistic impact on T cell activation higher than that for combo anti-Lag-3/anti-PD-(L)1. Studies still need to be continued to grasp more knowledge about the precise role of Lag-3 and its targeting in some cancer types including tumors of gastroesophageal area that show most of the controversies among different studies.