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Conclusion
It is clear that several uncharted territories exist in the map of LAG-3. These will require further
exploration if we are to fully exploit LAG-3 as a therapeutic target. We summarise these by raising
the following questions:
1. Do different LAG-3 ligands perform different roles, and if so, which LAG-3/ligand interactions
should be targeted in each scenario?
2. Will developing techniques finally enable the acquisition of the LAG-3
structure? If obtained, what light would this shed on LAG-3 interactions with its ligands or
on targeting strategies? Study of LAG-3 via Cryo-EM may be achievable as the size barrier is
lowered, however, engineering of novel LAG-3 constructs would be beneficial to both cryoEM and x-ray crystallography approaches.
3. Why does LAG-3 utilise multiple signalling motifs that are not observed in other immune
inhibitory receptors? The complexity and uniqueness of LAG-3 signalling leaves this
fundamental aspect of LAG-3 poorly understood and consequently more difficult to target.
Improving our understanding of LAG-3 signalling may provide further downstream targets
for therapeutic modulation.
4. Beyond arising as a result of the regulation of LAG-3 expression, does sLAG-3 possess a
function that is yet to be identified, and if so, what implications might this have for LAG-3
targeting therapies?
5. Might the LAG-3
-/-
phenotype hold more subtle traits that have not yet been observed and
could this phenotype hold the key to understanding the synergy between LAG-3 and PD-1
combinatorial blockade?
6. Can tumours ectopically express LAG-3, and if so, what implications might this have for LAG3 targeting therapies? Definition of LAG-3 expression and purpose on tumour cells might
reveal a novel insight about LAG-3 function.
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Accepted Manuscript
7. Is LAG-3 expressed in the brain and if so, on what cells is it expressed? Is it there by chance
or as a result of evolutionary motives? It is important to determine whether LAG-3 could be
a novel target for the treatment of conditions like PD.
Despite these mysteries, clinical trials targeting LAG-3 remain ongoing. Antibodies aimed at blocking
the LAG-3/MHC-II interaction are being tested in five active cancer immunotherapy clinical trials,
(NCT03365791, NCT03499899, NCT02460224, NCT02061761, NCT02658981) and 15 more are
currently recruiting at time of publication (19). In addition, an anti-PD-1/LAG-3 bispecific antibody
trial is also recruiting (NCT04140500) based on data that antibody targeting of PD-1 and LAG-3
synergistically inhibited tumour growth in vivo (90). So much remains to be answered in the exciting
field of LAG-3 biology,