title: LAG3 (CD223) as a cancer immunotherapy target.
abstract: Despite the impressive impact of CTLA4 and PD1-PDL1-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 (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3-targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 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.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Andrews
authors.affiliation: Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Marciscano
authors.affiliation: Departments of Oncology, Immunology and Urology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape; D059016:Tumor Microenvironment; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein
keywords: CD223; LAG3; cancer immunotherapy; immune regulation; inhibitory receptors; monoclonal antibodies; regulatory T cells