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

Abstract

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.

Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1

“…LAG3 was the only gene included in both signatures and, given the fact that it is a druggable target with agents under clinical development, we decided to explore its putative prognostic role [33]. We observed a positive association with favorable prognosis and a correlation with the presence of neutrophils and dendritic cells.…”

“…We observed a positive association with favorable prognosis and a correlation with the presence of neutrophils and dendritic cells. This finding is relevant as combinations of anti-PD1 and PD-L1 with anti-LAG3 therapies are currently in clinical development, [33] and mutations in RYR2 and AHNAK in these studies have not been evaluated yet.…”

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

“…All these results seemed to indicate that the high expression of LAG3 predicted a high malignant breast cancer. However, some studies had come to the seemingly opposite conclusion that high expression of LAG3 is associated with favorable overall survival in several solid tumors including ovarian, gastric, lymphoma, NSCLC, colorectal, and renal cancers (49), as well as in breast cancer. To make a reasonable explanation, we need to focus on the important immunologic role of LAG3.…”

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

“…More details on the role of the abovementioned biomarkers, viewed as therapeutic targets, as well as the currently available immune checkpoint inhibitors, and development and testing stages are presented in Table 2 [96][97][98][99][100][101][102][103][104].…”