ITPRIPL1 binds CD3ε to impede Tcell activation and enable tumor immune evasion.

Abstract

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 CD3ε, and its expression inhibits Tcells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on Tcells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial Tcell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted Tcell 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 Tcell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.