Prognostic Value of Lymphocyte-Activation Gene 3 (LAG3) in Cancer: A Meta-Analysis

Introduction: Therapeutic targeting of inhibitors of the immune response has reached the clinical setting. Inhibitors of the novel receptor LAG3, which negatively regulates T-cell activation, are under investigation. Here we explore the presence and prognostic role of LAG3 in cancer. Methods: A systematic search of electronic databases identified publications exploring the effect of LAG3 on overall survival (OS) and (for early-stage cancers) disease-free survival (DFS). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and random effect modeling. Subgroup analyses were conducted based on disease site and tumor type. Results: Fifteen studies met the inclusion criteria. LAG3 was associated with better overall survival [HR 0.81, 95% confidence interval (CI) 0.66-0.99; P = 0.04], with subgroup analysis showing no significant differences between disease-site subgroups. The beneficial effect of LAG3 on OS was of greater magnitude in early-stage malignancies (HR 0.73, 95% CI 0.60-0.88) than in the metastatic setting (HR 1.20, 95% CI 0.70-2.05), but this difference was not statistically significant (subgroup difference p = 0.18). LAG3 did not have a significant association with DFS [HR 1.02, 95% confidence interval (CI) 0.77-1.37; P = 0.87], with subgroup analysis showing worse DFS in patients with lymphoma and improved DFS in those with breast cancer. Conclusions: High expression of LAG3 is associated with favorable overall survival in several solid tumors. A trend toward an association in early-stage disease suggests the importance of immune surveillance in this setting.