LAG-3, TIM-3 and TIGIT: Checkpoints Beyond PD-1 and CTLA-4

Exhaustion and Co-Expression

When T cells are chronically stimulated by tumour antigen, they progressively lose function and upregulate multiple inhibitory receptors at once. LAG-3 dampens signalling through the T-cell receptor complex, TIM-3 is engaged by ligands including galectin-9 and phosphatidylserine, and TIGIT competes with the activating receptor CD226 for shared ligands.

Because these receptors act through partly non-overlapping mechanisms, blocking one in addition to PD-1 could in principle restore more T-cell function than blocking PD-1 alone.

Clinical Results So Far

The LAG-3 antibody relatlimab combined with nivolumab improved progression-free survival compared with nivolumab alone in untreated advanced melanoma, leading to approval of the combination. This is the first validation of a checkpoint beyond PD-1 and CTLA-4.

TIGIT blockade has had a harder path, with some large lung cancer trials failing to meet their endpoints. TIM-3 antibodies remain in earlier development. The field illustrates that a sound mechanism does not guarantee clinical benefit.

Interpretation Notes

Expression of LAG-3, TIM-3 or TIGIT on a tumour biopsy indicates T-cell exhaustion but is not an established predictive biomarker for any specific drug.

Adding checkpoints also tends to add immune-related toxicity, so combinations are weighed for benefit against risk.

Interpretation and Combination Toxicity

None of these receptors is a validated predictive biomarker. Their expression on a biopsy signals that the T-cell infiltrate is exhausted, which is consistent with — but not proof of — potential benefit from adding the corresponding antibody.

Each checkpoint added to PD-1 blockade tends to increase immune-related adverse events; the LAG-3 combination is no exception, though its toxicity has generally been closer to PD-1 monotherapy than to PD-1 plus CTLA-4. The TIGIT trial disappointments are a reminder that a strong preclinical rationale does not guarantee clinical benefit.

Key Takeaways

• ·LAG-3, TIM-3 and TIGIT are inhibitory receptors co-expressed on exhausted T cells.
• ·Relatlimab (anti-LAG-3) with nivolumab is approved in melanoma, the first checkpoint beyond PD-1 and CTLA-4.
• ·TIGIT and TIM-3 blockade have so far produced inconsistent trial results.