LAG3 (CD223) as a cancer immunotherapy target

Summary Despite the impressive impact of CTLA 4 and PD 1‐ PDL 1‐targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors ( IR s) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene‐3 ( LAG 3) ( CD 223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG 3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG 3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG 3 and interplay with other IR s remain largely unknown. However, the striking synergy between LAG 3 and PD 1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG 3 as compared with other IR s, highlights the potential uniqueness of LAG 3. There are now four LAG 3‐targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR . Given the translational relevance of LAG 3 and the heightened interest in the impact of dual LAG 3/ PD 1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.