Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1(+)TIM-3(+) T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3(+) cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T-reg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T-reg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon beta and gamma, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy. Galectin-9 regulates several cellular processes including TIM-3-mediated T cell death. Here the authors show that co-expressed PD-1 protects TIM-3(+) T cells from galectin-9-induced cell death and that anti-galectin-9 in combination with GITR agonism promotes an anti-tumor immune response.

Automated summary

The study reveals that PD-1 contributes to exhausted T cell survival by binding to TIM-3 ligand Gal-9 and inhibiting Gal-9/TIM-3 induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3(+) cytotoxic CD8 T cells and T-reg cells, while combination treatment with anti-Gal-9 and GITR agonist shows synergistic antitumor activity.