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Immunol Rev
2017[Mar]; 276
(1
): 80-96
PMID28258692
show ga
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.
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