ITPRIPL1 binds CD3epsilon
Menée à l'aide de lignées cellulaires, de modèles murins, de chiens présentant une tumeur solide (ostéosarcome, poumon, acanthome, cancer rhinopharyngé, mélanome) et d'échantillons tumoraux issus de patients, cette étude met en évidence un mécanisme par lequel la protéine ITRIPL1, en se liant à l'antigène CD3 epsilon, empêche l'activation des lymphocytes T et favorise l'échappement immunitaire de la tumeur
Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3
ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical “signal one” phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.
https://www.cell.com/cell/abstract/S0092-8674(24)00310-6 2023