Can a species-specific receptor-processing difference alter how preclinical anti-TIGIT antibody experiments are interpreted?
Human and macaque TIGIT behave differently when exposed to plasmin in the paper’s experiments. Rhesus peripheral blood mononuclear cells released soluble TIGIT after plasmin exposure. The shed ectodomain retained binding to CD155 and to a tested anti-TIGIT antibody, raising a specific model-interpretation concern.
TIGIT is an inhibitory receptor on immune cells. CD155 is one of its binding partners. Antibodies against TIGIT are investigated as checkpoint interventions, and macaques have been used in preclinical testing. A soluble receptor could bind ligand or antibody away from membrane TIGIT.
Figures in the original paper
Figures 1–3 — TIGIT cleavage, soluble ectodomain binding and antibody tests (external link)
Evidence and methods
The authors compared human and macaque TIGIT sequences and plasmin response, examined receptor shedding from rhesus and human PBMCs, and tested binding of the released TIGIT ectodomain to CD155 and tiragolumab. The exact sequence-to-cleavage relationship is discussed in the original paper.
Macaque TIGIT is plasmin-sensitive
The paper reports direct plasmin cleavage of macaque TIGIT under tested conditions, unlike the tested human receptor.
Rhesus cells release soluble TIGIT
Rhesus PBMCs, but not human PBMCs in the comparison, released soluble TIGIT after plasmin exposure.
The shed domain retains binding
The soluble ectodomain still bound CD155 and the tested antibody tiragolumab.
Antibody saturation did not stop shedding
Saturating the receptor with tested clinical anti-TIGIT antibodies did not prevent plasmin cleavage of rhesus TIGIT.
Inside the study
Why species comparison matters
A model can preserve TIGIT expression while changing how extracellular proteases process the receptor. The study tests a T119R-associated difference between macaque and human TIGIT under plasmin exposure.
Possible soluble sink
The released macaque ectodomain binds CD155 and tiragolumab in the reported assays. This supports a plausible ligand and antibody sink in that experimental setting; its effect on clinical trial outcomes remains unproven.
Practical interpretation
The result argues for measuring receptor shedding, protease context, and antibody binding when translating between macaque and human studies, rather than treating a shared target name as complete biological equivalence.
Interpretation
The authors propose that plasmin-generated soluble TIGIT may act as a binding sink in macaque experiments. The binding and shedding observations support that concern; they do not by themselves establish why any human clinical program succeeded or failed.
Evidence stage
This study is a mechanistic comparison relevant to preclinical model choice. It does not establish that macaques are invalid for every TIGIT study or prove a causal explanation of trial outcomes. The article appeared online November 20, 2025 and in the January 2026 issue.