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Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity

Burnell, Stephanie E. A., Capitani, Lorenzo, MacLachlan, Bruce J., Mason, Georgina H., Gallimore, Awen M. ORCID: and Godkin, Andrew ORCID: 2021. Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity. Immunotherapy Advances 2 (1) , ltab025. 10.1093/immadv/ltab025

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Despite three decades of research to its name and increasing interest in immunotherapies that target it, LAG-3 remains an elusive co-inhibitory receptor in comparison to the well-established PD-1 and CTLA-4. As such, LAG-3 targeting therapies have yet to achieve the clinical success of therapies targeting other checkpoints. This could, in part, be attributed to the many unanswered questions that remain regarding LAG-3 biology. Of these, we address: (i) the function of the many LAG-3-ligand interactions, (ii) the hurdles that remain to acquire a high-resolution structure of LAG-3, (iii) the under-studied LAG-3 signal transduction mechanism, (iv) the elusive soluble form of LAG-3, (v) the implications of the lack of (significant) phenotype of LAG-3 knockout mice, (vi) the reports of LAG-3 expression on the epithelium, and (vii) the conflicting reports of LAG-3 expression (and potential contributions to pathology) in the brain. These mysteries which surround LAG-3 highlight how the ever-evolving study of its biology continues to reveal ever-increasing complexity in its role as an immune receptor. Importantly, answering the questions which shroud LAG-3 in mystery will allow the maximum therapeutic benefit of LAG-3 targeting immunotherapies in cancer, autoimmunity and beyond.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
Publisher: Oxford University Press
ISSN: 2732-4303
Date of First Compliant Deposit: 14 April 2022
Date of Acceptance: 17 December 2021
Last Modified: 07 May 2023 13:36

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