Role of human lymphocyte activation gene 3 in tumor infiltrating lymphocytes

Among the various molecules that regulate T cell function, lymphocyte activation gene 3 (LAG- 3) has garnered significant interest. LAG-3 is expressed on activated T cells, B cells, NK cells, tumor infiltrating lymphocytes (TILs), and plasmacytoid dendritic cells. We previously showed that LAG-3 was relatively over-expressed on HA-specific transgenic T cells rendered anergic in vivo by encounter with cognate self antigen. In this system, regulatory activity could be functionally blocked with a LAG-3 specific monoclonal antibody (Huang et al). Observations in our lab using LAG-3 knockout mice demonstrate that CD8 T cells undergo enhanced homeostatic proliferation in vivo if LAG-3 is absent. Currently, we are conducting studies to understand the role of LAG-3 in human cancer. Via microarray, we compared CD4+25+GITR+ (Treg) T cells from the prostate to CD4+25-45RA+ (naïve) T cells from the peripheral blood. We found LAG-3 and CTLA-4 to be relatively upregulated in prostate infiltrating T regulatory cells. Also, at the expression level, we observed variable levels of LAG-3 expression on patient CD8 tumor infiltrating T lymphocytes (TILs). At a functional level, we have shown that a human anti-human LAG-3 antibody enhances T cell proliferation and cytokine function in a mixed lymphocyte reaction. Further studies that are currently underway suggest that LAG-3 could be a promising candidate for enhancing anti-tumor immunotherapy in a clinical setting.