Lag3: From Bench to Bedside

The introduction of immune checkpoint inhibitors represented a breakthrough treatment for metastatic melanoma, but the effect of these agents is not limited to a single cancer type. Promising results have been reported in various solid tumors, for example, lung cancer. The success of these drugs depends on the activation of tumor-infiltrating lymphocytes and primary and acquired resistance have been reported alongside a high rate of immune-related adverse events when agents targeting different immune checkpoints are given in combination. Numerous other targets have been investigated to overcome the resistance, improve the activity, and reduce the toxicity of checkpoint inhibitor therapy. Among these, the most promising is Lymphocyte-activation gene 3 (LAG-3), a transmembrane protein involved in cytokine release and inhibitory signaling in T cells. Preclinical data showed that LAG-3 is a negative regulator of both CD4⁺ T cell and CD8⁺ T cell and the activity on CD8⁺ T cell is independent of CD4⁺ activation. On the CD8⁺ T cell, LAG-3 activation abrogates the antigen presentation whereas on the CD4⁺ T cell, arrests the S phase of the cell cycle. The blockade of LAG-3 has been tested in several combination therapies, and recent clinical data showed a good safety profile and a synergistic effect with anti-PD-1, suggesting that this combination could become a standard treatment for metastatic melanoma. In this review, we report the available preclinical data and the new clinical data on LAG-3 blockade in different solid tumors, and we discuss LAG-3 as potential prognostic and predictive factor, together with possible future applications.