A checkpoint under active clinical investigation–initial setbacks highlight the need for better biomarkers.
TIGIT belongs to the CD28 family and delivers inhibitory signals through its ITIM domain. It binds CD155Loading... with higher affinity than the activating receptor DNAM-1 (CD226Loading...), creating a competitive balance similar to CTLA-4/CD28.
TIGIT is highly expressed on tumor-infiltrating T cells, particularly on regulatory T cellsLoading... (Tregs) and exhausted CD8+ T cells. It suppresses both T cell and NK cell anti-tumor activity.
Another Inhibitory Checkpoint: TIGIT on T and NK cells, when engaged by CD155 on tumor cells, suppresses immune activity. It's similar to PD-1 but works through different mechanisms.
Competition: TIGIT competes with the activating receptor CD226 for the same ligand (CD155). The balance determines net immune effect.
Tiragolumab (anti-TIGIT) showed promising Phase II results in combination with atezolizumab in PD-L1-high NSCLCLoading.... However, Phase III trials (SKYSCRAPER-01, -02) failed to meet primary endpoints.
These setbacks mirror the broader challenge in checkpoint development: identifying which patients will respond. Without biomarkers for TIGIT/CD155 engagement, trials include patients unlikely to benefit.
Mixed Results: Multiple anti-TIGIT drugs are in trials, often combined with PD-1/PD-L1 inhibitors. Results have been inconsistent.
The Question: Which patients have active TIGIT-mediated suppression that blocking would relieve? Better patient selection is needed.
The TIGIT/CD155 axis demonstrates why engagement biomarkers should be developed early in checkpoint programs. CD155 expression is widespread–present on many tumor types–but expression does not indicate functional immune suppression.
iFRETLoading... could quantify TIGIT/CD155 engagement in patient samples, potentially rescuing promising biology by identifying patients with active checkpoint suppression. This approach could differentiate between CD155-expressing tumors with and without TIGIT engagement.
The Opportunity: Measuring TIGIT/CD155 engagement (not just TIGIT expression) could identify patients most likely to benefit from anti-TIGIT therapy.
The Principle: If TIGIT isn't actively engaged, blocking it won't help—same principle validated for PD-1/PD-L1.
Theoretical Application: TIGIT/CD155 interaction represents another intercellular checkpoint amenable to iFRET. The balance between TIGIT/CD155 and CD226/CD155 engagement determines net immune activation or suppression–expression-based assayLoading...s cannot distinguish which interaction predominates.
QF-Pro could theoretically quantify engagement ratios, providing functional insight into immune regulatory balance.
Status: Theoretical application. Competing receptor paradigm presents unique measurement opportunity.
Future potential: TIGIT and CD226 compete for the same ligand (CD155). The ratio of engagement determines immune activation vs suppression. Expression can't distinguish which wins–QF-Pro could.
