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PMID: 28258692 Published · ppublish English Journal Article Review Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

LAG3 (CD223) as a cancer immunotherapy target.

Immunological reviews ·Vol. 276 ·No. 1 ·2017-00-00 ·Pages 80-96

Andrews LP, Marciscano AE, Drake CG, Vignali DA

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.

Keywords
CD223 LAG3 cancer immunotherapy immune regulation inhibitory receptors monoclonal antibodies regulatory T cells
MeSH Terms
Animals Antibodies, Monoclonal/therapeutic use Antigens, CD/genetics,immunology,metabolism Clinical Trials as Topic Disease Models, Animal Humans Immunotherapy/methods Lymphocyte Activation Mice Neoplasms/immunology,therapy Programmed Cell Death 1 Receptor/genetics,immunology,metabolism Signal Transduction T-Lymphocytes/immunology Tumor Escape Tumor Microenvironment
Chemicals
Antibodies, Monoclonal Antigens, CD CD223 antigen PDCD1 protein, human Programmed Cell Death 1 Receptor
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Andrews Lawrence P
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Marciscano Ariel E
Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Drake Charles G
Departments of Oncology, Immunology and Urology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Vignali Dario A A
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. | Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
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Article Info
Journal
Immunological reviews
Abbr.
Immunol Rev
ISSN
1600-065X
DOI
10.1111/imr.12519
Published
2017-00-00
Pages
80-96
Language
English
Region
England
NLM ID
7702118
PMCID
PMC5338468
Subset
IM
Grants
NCI NIH HHS · R01 CA154555 · United States
NCI NIH HHS · P30 CA006973 · United States
NCI NIH HHS · P30 CA047904 · United States
NCI NIH HHS · P50 CA097190 · United States
NIDDK NIH HHS · R01 DK089125 · United States
NIAID NIH HHS · P01 AI108545 · United States
External Links
PubMed source DOI: 10.1111/imr.12519 PMC Full Text View journal details
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